jwh-133 and Alzheimer-Disease

Topics: Adenylate Kinase; Aging; Alzheimer Disease; Aminoimidazole Carboxamide; Animals; Cannabinoids; Enzyme Activation; Gene Deletion; Glycogen Synthase Kinase 3 beta; Hippocampus; Memory; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Phosphorylation; Receptor, Cannabinoid, CB2; Resveratrol; Ribonucleotides; Signal Transduction; tau Proteins

The endocannabinoid CB2 receptor system has been implicated in the neuropathology of Alzheimer's disease (AD). In order to investigate the impact of the CB2 receptor system on AD pathology, a colony of mice with a deleted CB2 receptor gene, CNR2, was established on a transgenic human mutant APP background for pathological comparison with CB2 receptor-sufficient transgenic mice. J20 APP (PDGFB-APPSwInd) mice were bred over two generations with CNR2(-/-) (Cnr2(tm1Dgen)/J) mice to produce a colony of J20 CNR2(+/+) and J20 CNR2(-/-) mice. Seventeen J20 CNR2(+/+) mice (12 females, 5 males) and 16 J20 CNR2(-/-) mice (11 females, 5 males) were killed at 12 months, and their brains were interrogated for AD-related pathology with both biochemistry and immunocytochemistry (ICC). In addition to amyloid-dependent endpoints such as soluble Aβ production and plaque deposition quantified with 6E10 staining, the effect of CB2 receptor deletion on total soluble mouse tau production was assayed by using a recently developed high-sensitivity assay. Results revealed that soluble Aβ42 and plaque deposition were significantly increased in J20 CNR2(-/-) mice relative to CNR2(+/+) mice. Microgliosis, quantified with ionized calcium-binding adapter molecule 1 (Iba-1) staining, did not differ between groups, whereas plaque associated microglia was more abundant in J20 CNR2(-/-) mice. Total tau was significantly suppressed in J20 CNR2(-/-) mice relative to J20 CNR2(+/+) mice. The results confirm the constitutive role of the CB2 receptor system both in reducing amyloid plaque pathology in AD and also support tehpotential of cannabinoid therapies targeting CB2 to reduce Aβ; however, the results suggest that interventions may have a divergent effect on tau pathology.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Calcium-Binding Proteins; Cannabinoid Receptor Agonists; Cannabinoids; Disease Models, Animal; DNA-Binding Proteins; Female; Humans; Male; Mice, Transgenic; Microfilament Proteins; Microglia; Plaque, Amyloid; Polycomb-Group Proteins; Receptor, Cannabinoid, CB2; tau Proteins; Transcription Factors

Anandamide is an endocannabinoid involved in several physiological functions including neuroprotection. Anandamide is synthesized on demand and its endogenous level is regulated through its degradation, where fatty acid amide hydrolase plays a major role. The aim of this study was to characterize anandamide breakdown in physiological and pathological aging and its regulation by CB1 and CB2 receptor agonists. Fatty acid amide hydrolase activity was analyzed in an independent cohort of human cortical membrane samples from control and Alzheimer's disease patients, and in membrane and synaptosomes from adult and aged rat cerebral cortex. Our results demonstrate that fatty acid amide hydrolase activity decreases in the frontal cortex from human patients with Alzheimer's disease and this effect is mimicked by Aβ(1-40) peptide. This activity increases and decreases in aged rat cerebrocortical membranes and synaptosomes, respectively. Also, while the presence of JWH-133, a CB2 selective agonist, slightly increases anandamide hydrolysis in human controls, it decreases this activity in adults and aged rat cerebrocortical membranes and synaptosomes. In the presence of WIN55,212-2, a mixed CB1/CB2 agonist, anandamide hydrolysis increases in Alzheimer's disease patients but decreases in human controls as well as in adult and aged rat cerebrocortical membranes and synaptosomes. Although a similar profile is observed in fatty acid amide hydrolase activity between aged rat synaptic endings and human Alzheimer's disease brains, it is differently modulated by CB1/CB2 agonists. This modulation leads to a reduced availability of anandamide in Alzheimer's disease and to an increased availability of this endocannabinoid in aging.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amidohydrolases; Amyloid beta-Peptides; Animals; Arachidonic Acids; Benzamides; Benzoxazines; Cannabinoid Receptor Agonists; Cannabinoids; Carbamates; Case-Control Studies; Cerebral Cortex; Endocannabinoids; Enzyme Inhibitors; Female; Frontal Lobe; Humans; In Vitro Techniques; Male; Middle Aged; Morpholines; Naphthalenes; Polyunsaturated Alkamides; Rats; Rats, Wistar; Synaptosomes

The specific CB2 cannabinoid receptor agonist JWH-133 induced cognitive improvement in double AβPP/PS1 transgenic mice, a genetic model of Alzheimer's disease. This effect was more pronounced when administered at the pre-symptomatic rather than the early symptomatic stage. The cognitive improvement was associated with decreased microglial reactivity and reduced expression of pro-inflammatory cytokines IL-1β, IL-6, TNFα, and IFNγ. In addition, JWH-133 reduced the expression of active p38 and SAPK/JNK, increased the expression of inactive GSK3β, and lowered tau hyperphosphorylation at Thr181 in the vicinity of amyloid-β plaques. Moreover, JWH-133 produced a decrease in the expression of hydroxynonenal adducts, and enhanced the expression of SOD1 and SOD2 around plaques. In contrast, the chronic treatment with JWH-133 failed to modify the amyloid-β production or deposition in cortex and hippocampus. In conclusion, the present study lends support to the idea that stimulation of CB2 receptors ameliorates several altered parameters in Alzheimer's disease such as impaired memory and learning, neuroinflammation, oxidative stress damage and oxidative stress responses, selected tau kinases, and tau hyperphosphorylation around plaques.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Avoidance Learning; Cannabinoid Receptor Agonists; Cannabinoids; Cytokines; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Glycogen Synthase Kinase 3; Humans; Immunohistochemistry; Mice; Mice, Transgenic; Oxidative Stress; Plaque, Amyloid; Presenilin-1; Psychomotor Performance; Receptor, Cannabinoid, CB2; Recognition, Psychology; RNA; Synaptophysin; tau Proteins

Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.. We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on ¹⁸F-fluoro-deoxyglucose (¹⁸FDG) uptake by positron emission tomography (PET).. Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased ¹⁸FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.. In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Benzoxazines; Cannabinoids; Choroid Plexus; Cognition Disorders; Corpus Striatum; Cyclooxygenase 2; Disease Models, Animal; Encephalitis; Enzyme-Linked Immunosorbent Assay; Fluorodeoxyglucose F18; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Mice; Mice, Transgenic; Microglia; Morpholines; Naphthalenes; Positron-Emission Tomography; Receptor, Cannabinoid, CB2; RNA, Messenger; Time Factors

Alzheimer's disease (AD) is characterized by enhanced beta-amyloid peptide (betaA) deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits. Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after betaA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2, together with markers of microglial activation, and that CB1-positive neurons, present in high numbers in control cases, are greatly reduced in areas of microglial activation. In pharmacological experiments, we found that G-protein coupling and CB1 receptor protein expression are markedly decreased in AD brains. Additionally, in AD brains, protein nitration is increased, and, more specifically, CB1 and CB2 proteins show enhanced nitration. Intracerebroventricular administration of the synthetic cannabinoid WIN55,212-2 to rats prevent betaA-induced microglial activation, cognitive impairment, and loss of neuronal markers. Cannabinoids (HU-210, WIN55,212-2, and JWH-133) block betaA-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor-alpha release; these effects are independent of the antioxidant action of cannabinoid compounds and are also exerted by a CB2-selective agonist. Moreover, cannabinoids abrogate microglia-mediated neurotoxicity after betaA addition to rat cortical cocultures. Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzoxazines; Cannabinoids; Cells, Cultured; Coculture Techniques; Dronabinol; Female; Humans; Injections, Intraventricular; Male; Maze Learning; Microglia; Middle Aged; Morpholines; Motor Activity; Naphthalenes; Nerve Degeneration; Neurons; Neuroprotective Agents; Nitric Oxide; Peptide Fragments; Plaque, Amyloid; Protein Processing, Post-Translational; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction; Tumor Necrosis Factor-alpha