minocycline and Alzheimer-Disease

The novel antibiotic-exploiting strategy in the treatment of Alzheimer's (AD) and Parkinson's (PD) disease has emerged as a potential breakthrough in the field. The research in animal AD/PD models provided evidence on the antiamyloidogenic, anti-inflammatory, antioxidant and antiapoptotic activity of tetracyclines, associated with cognitive improvement. The neuroprotective effects of minocycline and doxycycline in animals initiated investigation of their clinical efficacy in AD and PD patients which led to inconclusive results and additionally to insufficient safety data on a long-standing doxycycline and minocycline therapy in these patient populations. The safety issues should be considered in two levels; in AD/PD patients (particularly antibiotic-induced alteration of gut microbiota and its consequences), and as a world-wide threat of development of bacterial resistance to these antibiotics posed by a fact that AD and PD are widespread incurable diseases which require daily administered long-lasting antibiotic therapy. Recently proposed subantimicrobial doxycycline doses should be thoroughly explored for their effectiveness and long-term safety especially in AD/PD populations. Keeping in mind the antibacterial activity-related far-reaching undesirable effects both for the patients and globally, further work on repurposing these drugs for a long-standing therapy of AD/PD should consider the chemically modified tetracycline compounds tailored to lack antimicrobial but retain (or introduce) other activities effective against the AD/PD pathology. This strategy might reduce the risk of long-term therapy-related adverse effects (particularly gut-related ones) and development of bacterial resistance toward the tetracycline antibiotic agents but the therapeutic potential and desirable safety profile of such compounds in AD/PD patients need to be confirmed.

Topics: Alzheimer Disease; Animals; Anti-Bacterial Agents; Doxycycline; Drug Repositioning; Humans; Minocycline; Parkinson Disease; Tetracycline

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer's disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

Topics: Alzheimer Disease; Animals; Dapsone; Drug Therapy, Combination; Humans; Ibuprofen; Inflammation; Minocycline; Neuroprotective Agents; Thalidomide

Despite advances in understanding the pathophysiology of Alzheimer's disease (AD), its therapy remains largely symptomatic and supportive. Acetylcholinesterase inhibitors - the first-line drugs used today do not prevent and treat AD. So far, over 90 Phase 3 trials of AD have been unsuccessful with 99.0% failure rate. There is, therefore, an urgent need to find effective new therapies for AD. Owing to the multifactorial nature of AD pathogenesis, polypharmacy with drugs that target heterogeneous pathophysiological pathways, needs to be considered. Fortunately, several drugs used currently in clinical use as monotherapies can be exploited in AD. This article, therefore, presents a novel pharmacological treatment paradigm and recommends the use of valuable diseasemodifying approved drugs, viz. melatonin, minocycline, modafinil, and memantine (the "M" Drugs). Melatonin - a neuroprotector is an antioxidant and anti-inflammatory. Minocycline is also neuroprotective, it reduces neuroinflammation and CNS pathology and prevents cell death. Sleep deprivation leads to decreased hippocampal neurogenesis, increased amyloid beta generation, and causes memory dysfunction. Modafinil - a wake-promoting agent is approved for use in narcolepsy and obstructive sleep apnea. It improves global mental status, hippocampal neurogenesis, attention, and cognition. Memantine is an uncompetitive N-methyl-d-aspartic acid receptor antagonist and is approved for the management of moderate-to-severe AD. The paramount possible beneficial effects of the M-drugs may include significant memory and cognitive enhancement in aging, mild cognitive impairment, and AD. The M drugs-centric pharmacotherapy strategy is comprehensive and pragmatic and is meant to combat multiple pathological targets and ameliorate cognitive dysfunction/AD.

Topics: Alzheimer Disease; Animals; Benzhydryl Compounds; Cognitive Dysfunction; Humans; Melatonin; Memantine; Minocycline; Modafinil

Alzheimer's disease (AD) is a neurodegenerative disorder where the main risk factor is age, since its incidence increases dramatically after the age of 60. It is the most common form of dementia, and is accompanied by memory loss and cognitive impairment. Although AD was discovered over a century ago, the only drugs approved by the US Food and Drug Administration for use in its treatment are four cholinesterase inhibitors and memantine. However, these drugs are not fully effective in the treatment of AD. Therefore, the incessant search for new methods of treating AD continues, with the hope of improving both the effectiveness of therapies and the quality of life for patients suffering with AD. Current evidence suggests that the antibiotic minocycline could be a potential therapeutic drug for use in the treatment of AD due to its anti-neuroinflammatory effects. Minocycline is a tetracycline derivative that combines an anti-inflammatory property that is capable of crossing the blood brain barrier with neuroprotective properties that work by limiting inflammation and oxidative stress. Several studies have established the presence of inflammatory markers in the brains of patients suffering with AD, including elevated levels of cytokines/chemokines and microgliosis in damaged regions. Cytokines have been associated with increased tau phosphorylation and decreased levels of synaptophysin, establishing their roles in the cytoskeletal and synaptic alterations that take place in AD. Therefore, pharmacological approaches that allow for the discovery and development of new anti-inflammatory agents such as minocycline will be welcomed in the continuing struggle against AD. Considering these facts, this review will discuss the anti-inflammatory mechanisms underlying the neuroprotective effects of minocycline as a novel therapeutic approach for the treatment of AD.

Topics: Alzheimer Disease; Animals; Humans; Inflammation; Minocycline

Sphingolipids represent a major class of lipids in which selected family members act as bioactive molecules that control diverse cellular processes, such as proliferation, differentiation, growth, senescence, migration and apoptosis. Emerging evidence reveals that sphingomyelinase/ceramide pathway plays a pivotal role in neurodegenerative diseases that involve mitochondrial dysfunction, oxidative stress and apoptosis. Minocycline, a semi-synthetic second-generation tetracycline derivative in clinical use for infection control, is also considered an effective protective agent in various neurodegenerative diseases in pre-clinical studies. Acting via multiple mechanisms, including anti-inflammatory, anti-oxidative and anti-apoptotic effects, minocycline is a desirable candidate for clinical trials in both acute brain injury as well as chronic neurodegenerative disorders. This review is focused on the anti-apoptotic and anti-oxidative mechanisms of minocycline against neurotoxicity induced by sphingomyelinase/ceramide in relation to neurodegeneration, particularly Alzheimer's disease and cerebral ischemia.

Topics: Alzheimer Disease; Antioxidants; Apoptosis; Brain Ischemia; Ceramides; Cyclic GMP; Humans; Minocycline; Mitochondria; Nitric Oxide; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sphingomyelin Phosphodiesterase; Thioredoxins

There are no disease-modifying treatments for Alzheimer disease (AD), the most common cause of dementia. Minocycline is anti-inflammatory, protects against the toxic effects of β-amyloid in vitro and in animal models of AD, and is a credible repurposed treatment candidate.. To determine whether 24 months of minocycline treatment can modify cognitive and functional decline in patients with mild AD.. Participants were recruited into a double-blind randomized clinical trial from May 23, 2014, to April 14, 2016, with 24 months of treatment and follow-up. This multicenter study in England and Scotland involved 32 National Health Service memory clinics within secondary specialist services for people with dementia. From 886 screened patients, 554 patients with a diagnosis of mild AD (Standardised Mini-Mental State Examination [sMMSE] score ≥24) were randomized.. Participants were randomly allocated 1:1:1 in a semifactorial design to receive minocycline (400 mg/d or 200 mg/d) or placebo for 24 months.. Primary outcome measures were decrease in sMMSE score and Bristol Activities of Daily Living Scale (BADLS), analyzed by intention-to-treat repeated-measures regression.. Of 544 eligible participants (241 women and 303 men), the mean (SD) age was 74.3 (8.2) years, and the mean (SD) sMMSE score was 26.4 (1.9). Fewer participants completed 400-mg minocycline hydrochloride treatment (28.8% [53 of 184]) than 200-mg minocycline treatment (61.9% [112 of 181]) or placebo (63.7% [114 of 179]; P < .001), mainly because of gastrointestinal symptoms (42 in the 400-mg group, 15 in the 200-mg group, and 10 in the placebo group; P < .001), dermatologic adverse effects (10 in the 400-mg group, 5 in the 200-mg group, and 1 in the placebo group; P = .02), and dizziness (14 in the 400-mg group, 3 in the 200-mg group, and 1 in the placebo group; P = .01). Assessment rates were lower in the 400-mg group: 68.4% (119 of 174 expected) for sMMSE at 24 months compared with 81.8% (144 of 176) for the 200-mg group and 83.8% (140 of 167) for the placebo group. Decrease in sMMSE scores over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points). The combined minocycline group had mean sMMSE scores 0.1 points higher than the placebo group (95% CI, -1.1 to 1.2; P = .90). The decrease in mean sMMSE scores was less in the 400-mg group than in the 200-mg group (3.3 vs 4.7 points; treatment effect = 1.2; 95% CI, -0.1 to 2.5; P = .08). Worsening of BADLS scores over 24 months was similar in all groups: 5.7 in the 400-mg group, 6.6 in the 200-mg group, and 6.2 in the placebo groups (treatment effect for minocycline vs placebo = -0.53; 95% CI, -2.4 to 1.3; P = .57; treatment effect for 400 mg vs 200 mg of minocycline = -0.31; 95% CI, -0.2 to 1.8; P = .77). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data.. Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. This study also found that 400 mg of minocycline is poorly tolerated in this population.. isrctn.org Identifier: ISRCTN16105064.

Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Minocycline; Neuroprotective Agents; Treatment Outcome

Alzheimer's disease (AD), as an advanced neurodegenerative disease, is characterized by the everlasting impairment of memory, which is determined by hyperphosphorylation of intracellular Tau protein and accumulation of beta-amyloid (Aβ) in the extracellular space. Minocycline is an antioxidant with neuroprotective effects that can freely cross the blood-brain barrier (BBB). This study investigated the effect of minocycline on the changes in learning and memory functions, activities of blood serum antioxidant enzymes, neuronal loss, and the number of Aβ plaques after AD induced by Aβ in male rats. Healthy adult male Wistar rats (200-220g) were divided randomly into 11 groups (n = 10). The rats received minocycline (50 and 100 mg/kg/day; per os (P.O.)) before, after, and before/after AD induction for 30 days. At the end of the treatment course, behavioral performance was measured by standardized behavioral paradigms. Subsequently, brain samples and blood serum were collected for histological and biochemical analysis. The results indicated that Aβ injection impaired learning and memory performances in the Morris water maze test, reduced exploratory/locomotor activities in the open field test, and enhanced anxiety-like behavior in the elevated plus maze. The behavioral deficits were accompanied by hippocampal oxidative stress (decreased glutathione (GSH) peroxidase enzyme activity and increased malondialdehyde (MDA) levels in the brain (hippocampus) tissue), increased number of Aβ plaques, and neuronal loss in the hippocampus evidenced by Thioflavin S and H&E staining, respectively. Minocycline improved anxiety-like behavior, recovered Aβ-induced learning and memory deficits, increased GSH and decreased MDA levels, and prevented neuronal loss and the accumulation of Aβ plaques. Our results demonstrated that minocycline has neuroprotective effects and can reduce memory dysfunction, which are due to its antioxidant and anti-apoptotic effects.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Disease Models, Animal; Hippocampus; Male; Maze Learning; Memory Disorders; Minocycline; Neurodegenerative Diseases; Neuroprotective Agents; Rats; Rats, Wistar

Neuroinflammation in Alzheimer's disease (AD) can occur due to excessive activation of microglia in response to the accumulation of amyloid-β peptide (Aβ). Previously, we demonstrated an increased expression of this peptide in the locus coeruleus (LC) in a sporadic model for AD (streptozotocin, STZ; 2 mg/kg, ICV). We hypothesized that the STZ-AD model exhibits neuroinflammation, and treatment with an inhibitor of microglia (minocycline) can reverse the cognitive, respiratory, sleep, and molecular disorders of this model.. To evaluate the effect of minocycline treatment in STZ model disorders.. We treated control and STZ-treated rats for five days with minocycline (30 mg/kg, IP) and evaluated cognitive performance, chemoreflex response to hypercapnia and hypoxia, and total sleep time. Additionally, quantification of Aβ, microglia analyses, and relative expression of cytokines in the LC were performed.. Minocycline treatment improved learning and memory, which was concomitant with a decrease in microglial cell density and re-establishment of morphological changes induced by STZ in the LC region. Minocycline did not reverse the STZ-induced increase in CO2 sensitivity during wakefulness. However, it restored the daytime sleep-wake cycle in STZ-treated animals to the same levels as those observed in control animals. In the LC, levels of A and expression of Il10, Il1b, and Mcp1 mRNA remained unaffected by minocycline, but we found a strong trend of minocycline effect on Tnf- α.. Our findings suggest that minocycline effectively reduces microglial recruitment and the inflammatory morphological profile in the LC, while it recovers cognitive performance and restores the sleep-wake pattern impaired by STZ.

Topics: Alzheimer Disease; Animals; Cognition; Cognitive Dysfunction; Disease Models, Animal; Maze Learning; Microglia; Minocycline; Neuroinflammatory Diseases; Rats; Sleep; Sleep Wake Disorders; Streptozocin

Minocycline has multiple neuroprotective roles in abundant brain diseases, including the prevention and treatment of Alzheimer's disease (AD). Cdk5/p25 signaling plays an important role in the onset and development of Alzheimer's-like pathology. The aim of the present work was to further explore the underlying mechanism which minocycline effects on Cdk5/p25 signaling related to Alzheimer's-like pathology.. The cognitive function of animals was measured by the Morris water maze test. The levels of Aβ were determined by an enzyme-linked immunosorbent assay. The levels of APP, β- and γ- secretases, and the biomarkers of tau (total tau and hyperphosphorylated tau), inflammatory cytokine and matrix metalloproteinases (MMP-2 and MMP-9), and biomarkers of synapse and Cdk5/p25 signaling, were detected by the Western blotting. The biomarkers of the synapse, inflammatory cytokine, and matrix metalloproteinases (MMP-2 and MMP-9) were also determined by immunofluorescence.. Minocycline improved learning and memory in APP/PS1 mice. It limited the production of Aβ and hyperphosphorylation of tau in the hippocampus and ameliorated synaptic deficit. Moreover, it also inhibited the activation of Cdk5/p25 signaling, inflammation, and matrix metalloproteinases.. Minocycline mitigates Alzheimer's-like pathology via limiting the activation of Cdk5/p25 signaling pathway and improves cognitive deficits.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Biomarkers; Cyclin-Dependent Kinase 5; Cytokines; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Minocycline; Phosphorylation; Phosphotransferases; Signal Transduction; tau Proteins

The aim of this study was to evaluate the effect of minocycline preadministration on cognitive dysfunction, hippocampal inflammatory response, and hippocampal senile dementia-related proteins induced by propofol anesthesia in aged rats. Sixty male SD rats, aged 20 months and weighing 340-410 g, were randomly divided into three groups: normal saline (NC) group, propofol group (prop), and minocycline (M) group. Prop group rats were injected intraperitoneally with 100 mg/kg propofol. The rats in group M were injected intraperitoneally with 50 mg/kg minocycline 30 minutes before injection of 100 mg/kg propofol, and the rest were the same as prop group. The rats in NC group were received intraperitoneal injection of the same amount of normal saline. The results indicated that compared with group C, the expressions of GSK-3

Topics: Alzheimer Disease; Anesthesia; Animals; Cognitive Dysfunction; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Interleukin-6; Male; Minocycline; NF-kappa B; Propofol; Rats; Rats, Sprague-Dawley; Saline Solution; Tumor Necrosis Factor-alpha

Neurodegenerative diseases are still a challenge for effective treatments. The high cost of approved drugs, severity of side effects, injection site pain, and restrictions on drug delivery to the Central Nervous System (CNS) can overshadow the management of these diseases. Due to the chronic and progressive evolution of neurodegenerative disorders and since there is still no cure for them, new therapeutic strategies such as the combination of several drugs or the use of existing drugs with new therapeutic applications are valuable strategies. Tetracyclines are traditionally classified as antibiotics. However, in this class of drugs, doxycycline and minocycline exhibit also anti-inflammatory effects by inhibiting microglia/macrophages. Hence, they have been studied as potential agents for the treatment of neurodegenerative diseases. The results of in vitro and in vivo studies confirm the effective role of these two drugs as anti-inflammatory agents in experimentally induced models of neurodegenerative diseases. In clinical studies, satisfactory results have been obtained in Multiple sclerosis (MS) but not yet in other disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), or Amyotrophic lateral sclerosis (ALS). In recent years, researchers have developed and evaluated nanoparticulate drug delivery systems to improve the clinical efficacy of these two tetracyclines for their potential application in neurodegenerative diseases. This study reviews the neuroprotective roles of minocycline and doxycycline in four of the main neurodegenerative disorders: AD, PD, ALS and MS. Moreover, the potential applications of nanoparticulate delivery systems developed for both tetracyclines are also reviewed.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Anti-Bacterial Agents; Doxycycline; Drug Delivery Systems; Humans; Minocycline; Nanoparticle Drug Delivery System; Neurodegenerative Diseases; Parkinson Disease

Minocycline hydrochloride is a semi-synthetic, second-generation tetracycline with neuroprotective, neurorestorative, anti-amyloidogenic, anti-inflammatory, antioxidant, and anti-apoptotic properties. The present study was designed to investigate the potential protective effects of minocycline against beta-amyloid (Aβ)-induced Alzheimer's disease (AD), recognition memory decline, and the possible involved anti-apoptotic mechanisms.. The rats were treated with minocycline (50 and 100 mg/kg/day; P.O.) after AD induction for 30 days. Behavioral functions were assessed by employing standard behavioral tests, including novel object recognition (NOR) and passive avoidance learning (PAL) tasks. Then, total antioxidant capacity (TAC) and total oxidant status (TOS) were measured in blood serum using ELISA kits. Apoptosis and the number of Aβ plaques were examined by the TUNEL and Congo red staining, respectively.. Treatment of Aβ rats with minocycline improved memory deficit in the PAL task and a decline in recognition memory in the NOR test. Minocycline at 50 and 100 mg/kg significantly reduced the TOS levels and increased the TAC levels (P < 0.0001). Also, minocycline at 50 and 100 mg/kg reduced the apoptotic index in the hippocampus of Aβ rats. After Congo red staining, the minocycline group showed improved cell morphology and markedly fewer Aβ plaques.. Minocycline reduced memory and learning deficit in behavioral experiments after Aβ injection, which may be due to its anti-inflammatory and anti-apoptotic effects.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Antioxidants; Avoidance Learning; Congo Red; Disease Models, Animal; Hippocampus; Male; Minocycline; Peptide Fragments; Plaque, Amyloid; Rats

Minocycline, a semisynthetic tetracycline-derived antibiotic, has various pharmacological effect such as anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects. The current study investigated the involvement of neuro-inflammatory, oxidative stress, and cholinergic markers in neuroprotection by minocycline against scopolamine-induced brain damage.. Minocycline was administered (oral, 10, 15, and 30 mg/kg, daily) to groups of amnesic rats for 21 days. Passive avoidance memory and spatial learning and memory were assessed. Following that, oxidative stress, cholinergic function, and neuro-inflammation markers were evaluated in the brain tissue.. According to our biochemical data, treatment of the scopolamine-injured rats with minocycline decreased the levels of malondialdehyde and acetylcholinesterase (AChE) as well as mRNA expression of AChE and neuro-inflammation markers (tumor necrosis factor-α, interleukin (IL)-1β, IL-6). It also increased the total thiol levels and superoxide dismutase activity as well as mRNA expression of cholinergic receptor M1 (ChRM1). Moreover, minocycline modified distance and latencies in Morris water maze, prolonged latency to enter the black zone and light time while decreasing time spent and frequency of entries to darkness.. Taken together, the data indicate that treatment with minocycline improved memory dysfunction mediated possibly through restoring AChE and ChRM1 levels, oxidant/antioxidant balance, as well as inhibiting inflammatory responses.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinergic Agents; Cognitive Dysfunction; Inflammation; Maze Learning; Minocycline; Rats; RNA, Messenger; Scopolamine

Topics: Alzheimer Disease; Humans; Minocycline

Topics: Alzheimer Disease; Humans; Minocycline; Research Design; Semantics

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Humans; Minocycline

Topics: Alzheimer Disease; Anti-Bacterial Agents; Humans; Minocycline

Topics: Alzheimer Disease; Anti-Bacterial Agents; Humans; Minocycline

Considerable clinical and experimental studies have shown that depression-related disorders are the most common neuropsychiatric symptoms in Alzheimer's disease (AD), affecting as many as 20-40% of patients. An increasing amount of evidence shows that monoamine-based antidepressant treatments are not completely effective for depression treatment in patients with dementia. Minocycline, a second-generation tetracycline antibiotic, has been gaining research and clinical attention for the treatment of different neuropsychiatric disorders, and more recently depression symptom in humans.. In the present study, we investigated the effects of Aβ1-42 administration alone or in combination with minocycline treatment on depression-like behaviors and anti/pro-inflammatory cytokines such as interleukin(IL)-10, IL-β, and tumor necrosis factor (TNF)-α in the hippocampus of rats.. Our results showed that Aβ1-42 administration increased depression-related behaviors in sucrose preference test, tail suspension test, novelty-suppressed feeding test, and forced swim test. We also found significant increases in IL-1β and TNF-α levels in the hippocampus of Aβ1-42-treated rats. Interestingly, minocycline treatment significantly reversed depression-related behaviors and the levels of hippocampal cytokines in Aβ1-42-treated rats.. These findings support the idea that there is a significant relationship among AD, depression-related symptoms, and pro-inflammatory cytokines in the brain, and suggest that antidepressant-like impacts of minocycline could be due to its anti-inflammatory properties. This drug could be of potential interest for the treatment of depression in patients with Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antidepressive Agents; Cytokines; Depression; Disease Models, Animal; Hindlimb Suspension; Hippocampus; Inflammation; Inflammation Mediators; Male; Minocycline; Peptide Fragments; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Topics: Alzheimer Disease; Animals; Clinical Medicine; Humans; Minocycline; Neuroprotective Agents

The search for novel therapies for the treatment of Alzheimer's disease is an urgent need, due to the current paucity of available pharmacological tools and the recent failures obtained in clinical trials. Among other strategies, the modulation of amyloid-triggered neuroinflammation by the endocannabinoid system seems of relevance. Previous data indicate that the enhancement of the endocannabinoid tone through the inhibition of the enzymes responsible for the degradation of their main endogenous ligands may render beneficial effects. Based on previously reported data, in which we described a paradoxical effect of the genetic deletion of the fatty acid amide hydrolase, we here aimed to expand our knowledge on the role of the endocannabinoid system in the context of Alzheimer's disease. To that end, we inhibited the production of interleukin-1β, one of the main inflammatory cytokines involved in the neuroinflammation triggered by amyloid peptides, in a transgenic mouse model of this disease by using minocycline, a drug known to impair the synthesis of this cytokine. Our data suggest that interleukin-1β may be instrumental in order to achieve the beneficial effects derived of fatty acid amide hydrolase genetic inactivation. This could be appreciated at the molecular (cytokine expression, amyloid production, plaque deposition) as well as behavioral levels (memory impairment). We here describe a previously unknown link between the endocannabinoid system and interleukin-1β in the context of Alzheimer's disease that open new possibilities for the development of novel therapeutics.

Topics: Alzheimer Disease; Amidohydrolases; Animals; Cytokines; Disease Models, Animal; Inflammation Mediators; Interleukin-1beta; Mice, Knockout; Mice, Transgenic; Microglia; Minocycline; Phenotype

Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer's disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.

Topics: Adult Children; Alzheimer Disease; Animals; Anti-Bacterial Agents; Behavior, Animal; Disease Models, Animal; Female; Humans; Immune System Phenomena; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Phagocytosis; Pregnancy; Schizophrenia; Synaptic Transmission; Transcriptome

Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer's disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder.. An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay.. These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein.. On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Diabetes Complications; Female; Hippocampus; Interleukin-1beta; Minocycline; Models, Animal; Neurogenic Inflammation; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; tau Proteins; Tumor Necrosis Factor-alpha

A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated.. To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway.. Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Neuropathies; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Animals, Newborn; Aspartic Acid Endopeptidases; Calcium-Binding Proteins; Cyclooxygenase 2; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Minocycline; Mutation; Neurogenic Inflammation; NFI Transcription Factors; Nitric Oxide Synthase Type II; Peptide Fragments

Activated microglia with macrophage-like functions invade and surround β-amyloid (Aβ) plaques in Alzheimer's disease (AD), possibly contributing to the turnover of Aβ, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis.. To determine the role of microglia on neurogenesis in brains with Aβ pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1).. Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of Aβ and Aβ-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice.. These results suggest a role for microglia in Aβ-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of Aβ pathology.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents; Cognition Disorders; Disease Models, Animal; Female; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Minocycline; Mutation; Neurogenesis; Presenilin-1

Topics: Alzheimer Disease; Animals; Anti-Bacterial Agents; Disease Models, Animal; Humans; Lipoxygenase Inhibitors; Mice; Mice, Transgenic; Microglia; Minocycline; Neuroprotective Agents; Nootropic Agents

Minocycline, a tetracycline antibiotic, has been reported to exert beneficial effects in models of Alzheimer's disease (AD). To characterize the mechanisms underlying the putative minocycline-related neuroprotection, we studied its effect in an in vitro model of AD. Primary hippocampal cultures were treated with β-amyloid peptide (Aβ) and cell viability was assessed by standard MTT-assay. Incubation with 10 μM Aβ for 24 h significantly inhibits cellular MTT-reduction without inducing morphological signs of enhanced cell death or increase in release of lactate dehydrogenase. This indicates that cell viability was not affected. The inhibition of MTT-reduction by Aβ was due to an acceleration of MTT-formazan exocytosis. Intriguingly, the Aβ-triggered increase in MTT-formazan exocytosis was abolished by co-treatment with minocycline. In vehicle-treated cells minocycline had no effect on formazan exocytosis. This hitherto unrecognized property of minocycline has to be noticed in the elucidation of the underlying mechanism of this promising neuroprotectant.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Cells, Cultured; Exocytosis; Formazans; Hippocampus; Humans; Minocycline; Neurons; Rats; Rats, Wistar; Tetrazolium Salts

Cognitive decline in Alzheimer's disease (AD) occurs as a result of the buildup of pathological proteins and downstream events including an elevated and altered inflammatory response. Inflammation has previously been linked to increased abnormal phosphorylation of tau protein. To determine if endogenous amyloid-beta (Abeta)-induced neuroinflammation drives tau phosphorylation in vivo, we treated 8-month-old 3xTg-AD with minocycline, an anti-inflammatory agent, to assess how it influenced cognitive decline and development of pathology. 4 months of treatment restored cognition to non-transgenic performance. Inflammatory profiling revealed a marked decrease in GFAP, TNFalpha, and IL6 and an increase in the CXCL1 chemokines KC and MIP1a. Minocycline also reduced levels of insoluble Abeta and soluble fibrils. Despite reducing levels of the tau kinase cdk5 coactivator p25, minocycline did not have wide effects on tau pathology with only one phospho-epitope showing reduction with treatment (S212/S214). The sum of these findings shows that reduction of the inflammatory events in an AD mouse model prevents cognitive deficits associated with pathology, but that endogenous Abeta-derived neuroinflammation does not contribute significantly to the development of tau pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Cognition; Disease Models, Animal; Encephalitis; Maze Learning; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Minocycline; Phosphorylation; Recognition, Psychology; tau Proteins; Tauopathies

Alzheimer's disease (AD) is characterized by the presence of neurofibrillary tangles of hyperphosphorylated, aggregated tau protein and extracellular deposits of beta-amyloid peptide. Increased beta-amyloid levels are thought to precede tangle formation, but tau pathology is more closely related to neuronal death. Minocycline, a tetracycline derivative, has potent antiinflammatory, antiapoptotic, and neuroprotective effects in several models of neurodegenerative disease, including models of AD with amyloid pathology. We have used both in vitro and in vivo models of AD to determine whether minocycline may have therapeutic efficacy against tau pathology. In primary cortical neurons, minocycline prevents beta-amyloid-induced neuronal death, reduces caspase-3 activation, and lowers generation of caspase-3-cleaved tau fragments. Treatment of tangle-forming transgenic mice (htau line) with minocycline results in reduced levels of tau phosphorylation and insoluble tau aggregates. The in vivo effects of minocycline are also associated with reduced caspase-3 activation and lowered tau cleavage by caspase-3. In tau mice, we find that conformational changes in tau are susceptible to minocycline treatment, but are not directly associated with the amount of tau fragments produced, highlighting a dissociation between the development of these pathological tau species. These results suggest a possible novel therapeutic role for minocycline in the treatment of AD and related tauopathies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Caspase 3; Cell Death; Cells, Cultured; Glutamic Acid; Humans; Mice; Mice, Transgenic; Minocycline; Neurons; Rats; Staurosporine; tau Proteins; Time Factors

We previously reported that the precursor form of nerve growth factor (pro-NGF) and not mature NGF is liberated in the CNS in an activity-dependent manner, and that its maturation and degradation occur in the extracellular space by the coordinated action of proteases.Here, we present evidence of diminished conversion of pro-NGF to its mature form and of greater NGF degradation in Alzheimer disease (AD) brain samples compared with controls. These alterations of the NGF metabolic pathway likely resulted in the increased pro-NGF levels. The pro-NGF was largely in a peroxynitrited form in the AD samples. Intrahippocampal injection of amyloid-beta oligomers provoked similar upregulation of pro-NGF in naive rats that was accompanied by evidence of microglial activation (CD40), increased levels of inducible nitric oxide synthase, and increased activity of the NGF-degrading enzyme matrix metalloproteinase 9. The elevated inducible nitric oxide synthase provoked the generation of biologically inactive, peroxynitrite-modified pro-NGF in amyloid-beta oligomer-injected rats. These parameters were corrected by minocycline treatment. Minocycline also diminished altered matrix metalloproteinase 9, inducible nitric oxide synthase, and microglial activation (CD40); improved cognitive behavior; and normalized pro-NGF levels in a transgenic mouse AD model. The effects of amyloid-beta amyloid CNS burden on NGF metabolism may explain the paradoxical upregulation of pro-NGF in AD accompanied by atrophy of forebrain cholinergic neurons.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; CD40 Antigens; Disease Models, Animal; Female; Humans; Immunoprecipitation; Male; Matrix Metalloproteinase 9; Maze Learning; Mice; Mice, Transgenic; Minocycline; Nerve Growth Factor; Nerve Growth Factors; Nitric Oxide Synthase Type II; Peptide Fragments; Peroxynitrous Acid; Protein Precursors; Rats; Rats, Inbred F344; Reaction Time; Tyrosine; Up-Regulation

Bone marrow (BM)-derived monocytes contribute to the development of microglial reaction around beta-amyloid (Abeta) plaques in Alzheimer's disease (AD) and possibly clear Abeta. Therefore, it is of great importance to separate the proinflammatory actions of monocytic cells from Abeta phagocytic effects. We used minocycline (mino) to systemically downregulate microglial activation and studied proliferation, expression of markers for activated microglia, and Abeta removal in vitro and in vivo. Mino did not affect proliferation or phagocytic activity of BM-derived cells toward Abeta in vitro. Intrahippocampal LPS injection used to induce inflammation and increase recruitment of BM cells from periphery, reduced Abeta burden in BM-transplanted AD transgenic mice. All engrafted cells expressed CD45, approximately 50% expressed Iba-1, and <0.5% of these cells expressed CD3e. About 40% of the engrafted cells were mitotically active. LPS increased immunoreactivity for Iba-1, MHC II, a marker of antigen presenting cells, and CD68, a marker of lysosomal activity. The endogenous microglia largely contributed to these LPS-induced immunoreactivities. Mino reduced the engraftment of BM-derived cells and blocked the LPS-induced MHC II and Iba-1 immunoreactivities, but did not prevent the increased CD68-immunoreactivity or the reduced Abeta burden. Importantly, mino did not block the association of eGFP-positive cells with Abeta deposits and the percentage of mitotically active BM-derived cells. In conclusion, mino reduces overall inflammatory potential of BM-derived monocytic cells without preventing their phagocytic activity. The separation of harmful activation of microglia/monocytic cells from their Abeta clearing mechanism may hold important therapeutic potential.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Bacterial Agents; Biomarkers; Bone Marrow Transplantation; Disease Models, Animal; Encephalitis; Female; Graft Survival; Humans; Inflammation Mediators; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Minocycline; Monocytes; Phagocytosis

Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNA-dependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 alpha and caspase 12 activation induced by amyloid beta peptide1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 alpha were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid beta peptide(1-42)-infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid beta peptide(1-42)-infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 alpha is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Avoidance Learning; Brain; Case-Control Studies; Cell Death; Cognition Disorders; Disease Models, Animal; Humans; Male; Maze Learning; Mice; Mice, Transgenic; Minocycline; Nerve Growth Factor; Neurons; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Rats; Rats, Wistar; Transfection

Activated microglia and reactive astrocytes invade and surround cerebral beta amyloid (Abeta) plaques in Alzheimer's disease (AD), but the role of microglia in plaque development is still unclear. In this study, minocycline was administered for 3 months, prior to and early in Abeta plaque formation in amyloid precursor protein transgenic mice (APP-tg). When minocycline was given to younger mice, there was a small but significant increase in Abeta deposition in the hippocampus, concurrent with improved cognitive performance relative to vehicle treated mice. If APP-tg mice received minocycline after Abeta deposition had begun, microglial activation was suppressed but this did not affect Abeta deposition or improve cognitive performance. In vitro studies demonstrated that minocycline suppressed microglial production of IL-1beta, IL-6, TNF, and NGF. Thus, minocycline has different effects on Abeta plaque deposition and microglia activation depending on the age of administration. Our data suggest that this may be due to the effects of minocycline on microglial function. Therefore, anti-inflammatory therapies to suppress microglial activation or function may reduce cytokine production but enhance Abeta plaque formation early in AD.

Topics: Age Factors; Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Animals, Newborn; Anti-Bacterial Agents; Anti-Inflammatory Agents; Brain; Cell Line, Tumor; Cells, Cultured; Cognition; Cytokines; Disease Models, Animal; Encephalitis; Gliosis; Humans; Mice; Mice, Transgenic; Microglia; Minocycline; Plaque, Amyloid; Up-Regulation

Two prominent characteristics of Alzheimer's disease are basal forebrain cholinergic degeneration and neuroinflammation characterized by glial activation and the release of pro-inflammatory cytokines. Mu p75- saporin (SAP) is a novel immunotoxin that mimics the selective loss of basal forebrain cholinergic neurons and induces cognitive impairment in mice. We report that cholinergic cell loss in the medial septal nucleus and ventral diagonal band after i.c.v. injection of mu p75-SAP is accompanied by simultaneous activation of microglia and astrocytes in the basal forebrain region as well as significant memory loss. Consistent with a role of glial cells in the pathology of Alzheimer's disease, minocycline, a second-generation tetracycline with known anti-inflammatory and neuroprotective properties, attenuated mu p75-SAP-induced cholinergic cell loss, glial activation and transcription of downstream pro-inflammatory mediators. In addition to neuroprotection, minocycline treatment mitigated the cognitive impairment that appears to be a functional consequence of mu p75-SAP lesioning. The current study demonstrates that glial-related inflammation plays a significant role in the selective neurotoxicity of mu p75-SAP, and suggests that minocycline may provide a viable therapeutic option for degenerating cholinergic systems.

Topics: Alzheimer Disease; Animals; Astrocytes; Cholinergic Fibers; Disease Models, Animal; Gene Expression; Immunohistochemistry; Immunotoxins; Injections, Intraventricular; Interleukin-1; Macrophage Activation; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Microglia; Minocycline; N-Glycosyl Hydrolases; Nerve Degeneration; Neuroprotective Agents; Plant Proteins; Prosencephalon; Reverse Transcriptase Polymerase Chain Reaction; Ribosome Inactivating Proteins, Type 1; Saporins; Tumor Necrosis Factor-alpha