pitavastatin and Alzheimer-Disease

Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Autophagy; Cell Line, Tumor; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Humans; Mice; Neurofibrillary Tangles; Phosphorylation; Proteasome Endopeptidase Complex; Proteolysis; Quinolines; rho-Associated Kinases; Signal Transduction; tau Proteins; Tauopathies

To examine and compare the pleiotropic effects on oxidative stress and metabolic signaling pathways of atorvastatin and pitavastatin in mouse model of Alzheimer's disease (AD).. We gave the transgenic (Tg) mice either atorvastatin or pitavastatin from 5-20 months (M) of age, and performed immunohistological analysis [4-hydroxy-2-nonenal (4-HNE)-positive, advanced glycation end products (AGEs), low-density lipoprotein receptor (LDL-R)-positive neurons, apolipoprotein E (ApoE)-positive senile plaque (SP), and insulin receptor (IR)-positive endothelium], and biochemistry analysis (adiponectin and leptin).. The numbers of 4-HNE- and AGE-positive neurons and the sum of ApoE-positive SP size progressively increased with age in amyloid precursor protein (APP)-Tg mice, while the amount of IR-positive endothelium and the number of LDL-R-positive neurons decreased. Adiponectin and leptin serum levels were lower in APP-Tg mice than in non-Tg mice. Treatment with statins reduced the number of AGE-positive neurons from as early as 10 M, preserved the numbers of 4-HNE- and LDL-R-positive neurons and the amount of IR-positive endothelium at 15 M, and reduced the sum of ApoE-positive SP size and adiponectin serum level at 20 M.. Atorvastatin and pitavastatin reduced the level of oxidative stress, as revealed by the presence of 4-HNE and AGE, in AD mouse brains, and that treatment with statins improves insulin signaling and LDL-R/ApoE systems. The beneficial effects of these statins may be associated with direct pleiotropic effects on AD mouse brains, indirect effects through improving the serum adiponectin/leptin balance, or both.

Topics: Adiponectin; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Atorvastatin; Cerebral Cortex; Endothelium, Vascular; Female; Glycation End Products, Advanced; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leptin; Mice; Neurons; Oxidative Stress; Plaque, Amyloid; Pyrroles; Quinolines; Receptor, Insulin; Receptors, LDL

To examine and compare the pleiotropic anti-inflammatory effects and the long-term effects of atorvastatin and pitavasatin in mouse model of Alzheimer's disease (AD).. We examined the effects of two strong statins on senile plaque (SP) size and inflammatory responses in the brain of an amyloid precursor protein (APP) transgenic (Tg) mouse. We gave the Tg mice either atorvastatin or pitavastatin from 5-20 months of age, and performed immunohistological analysis [SP area, monocyte chemotactic protein 1 (MCP-1)-positive neurons, ionized calcium-binding adaptor molecule 1 (Iba-1)-1-positive microglia, and tumor necrosis factor α (TNF-α)-positive neurons] every 5 months.. In the APP-Tg mice treated with both statins, the number of MCP-1-positive neurons was reduced at 10 months, that of Iba-1-positive microglia was reduced at 15 months, and that of TNF-α-positive neurons and the mean total SP area decreased at 15-20 months, compared with APP-Tg mice with vehicle treatment.. The protective effect of these statins took 5 months to reach significance in these mice, and the order of sensitivity to statin treatment was MCP-1>Iba-1>TNF-α>SPs. Proinflammatory responses including MCP-1, Iba-1, and TNF-α preceded and possibly contributed to SP formation. Pitavastatin has the same significant pleiotrophic effect to prevent and ameliorate inflammation and also has a long-term effect compared with atorvastatin, and both of them have high potential for a preventative approach in patients at risk of AD.

Topics: Alzheimer Disease; Animals; Atorvastatin; Brain; Disease Models, Animal; Female; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Inflammation; Mice; Mice, Transgenic; Plaque, Amyloid; Pyrroles; Quinolines

Structural and functional abnormalities in the neurovascular unit (NVU) have been recently observed in Alzheimer's disease (AD). Statins, which are used clinically for reducing cholesterol levels, can also exert beneficial vascular actions, improve behavioral memory and reduce senile plaque (SP). Thus, we examined cognitive function, the serum level of lipids, senile plaque (SP), and the protective effects of statins on NVU disturbances in a mouse AD model. Amyloid precursor protein (APP) transgenic (Tg) mice were used as a model of AD. Atorvastatin (30 mg/kg/day, p.o.) or pitavastatin (3mg/kg/day, p.o.) were administered from 5 to 20 months of age. These 2 statins improved behavioral memory and reduced the numbers of SP at 15 and 20 M without affecting serum lipid levels. There was a reduction in immunopositive staining for N-acetyl glucosamine oligomer (NAGO) in the endothelium and in collagen IV in the APP vehicle (APP/Ve) group, with collagen IV staining most weakest near SP. There was also an increase in intensity and numbers of glial fibrillary acidic protein (GFAP) positive astrocytes, particularly around the SP, where MMP-9 was more strongly labeled. Double immunofluorescent analysis showed that astrocytic endfeet had detached from the capillary endothelium in the APP/Ve group. Overall, these data suggest that statins may have therapeutic potential for AD by protecting NVU.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Anticholesteremic Agents; Atorvastatin; Cholesterol; Collagen Type IV; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glial Fibrillary Acidic Protein; Glucosamine; Heptanoic Acids; Humans; Matrix Metalloproteinase 9; Maze Learning; Methylcellulose; Mice; Mice, Transgenic; Mutation; Pyrroles; Quinolines

In addition to simply reducing the serum level of cholesterol, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have various pleiotrophic effects such as reducing oxidative stress, neuroinflammation, and neurotoxicity. However, such a pleiotrophic effect has not been fully studied in a new statin (pitavastatin). We examined and compared the effects of two strong statins (atorvastatin, 30 mg/kg/day, p.o.; pitavastatin, 3mg/kg/day, p.o.) on the serum level of lipids, cognitive dysfunction, senile plaque (SP) and phosphorylated tau-positive dystrophic neuritis (pτDN) in amyloid precursor protein (APP) transgenic (Tg) mice from 5 months (M) of age to 20 M. These two statins improved behavioral memory and reduced the numbers of SP and pτDN at 15 and 20 M without affecting serum lipid levels, but preserved mice brain weight in pitavastatin group at 20 M. These protective effects of statins took 10 M from the beginning of treatment to show an improvement in the present model mice, and sensitivity to the statin treatment was linked to behavioral memory, SP and pτDN in this order. These findings suggest that early treatment with both atorvastatin and pitavastatin prevented subsequent worsening of cognitive function and the amyloidogenic process, probably due to pleiotrophic effects, suggesting a therapeutic potential for Alzheimer's disease (AD).

Topics: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Atorvastatin; Body Weight; Brain; Cognition Disorders; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Maze Learning; Mice; Mice, Transgenic; Neuroprotective Agents; Organ Size; Phosphorylation; Plaque, Amyloid; Protein Processing, Post-Translational; Pyrroles; Quinolines; tau Proteins

In contrast to cerebral cortical neurons, the extent of damage to cells of the cerebellum in Alzheimer's disease (AD) is still a matter of debate. Here, we examined pathological changes in the cerebellar Purkinje cells (PCs) of AD model mice (amyloid precursor protein transgenic (APP-Tg) mice) at 10, 15, and 20 months (M) of age, and investigated the possible protective effect of two strong statins (atorvastatin at 30 mg/kg/day or pitavastatin at 3mg/kg/day, p.o.) by administering these statins from 5 to 20 M. The number of PCs detected by hematoxylin-eosin staining in APP-Tg mice was approximately 60% of the number in non-Tg mice at 10 M, and this progressively reduced with age until 20 M. Moreover, the number of monocyte chemotactic protein 1 (MCP-1)-positive PCs and tumor necrosis factor alpha (TNF-α)-positive PCs was also reduced in the transgenics. In contrast, the APP-Tg mice treated with either of the two statins showed a significant recovery in the number of PCs, and MCP-1 (at 20 M) and TNF-α (at 15 and 20 M) staining in PCs was preserved. Because MCP-1 and TNF-α play important roles in maintaining the synaptic network in PCs, the present study suggests that atorvastatin and pitavastatin can maintain the number of PCs and their synaptic networks in the AD cerebellum.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Atorvastatin; Chemokine CCL2; Disease Models, Animal; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Mice; Mice, Transgenic; Purkinje Cells; Pyrroles; Quinolines; Tumor Necrosis Factor-alpha

Statins, long known to be beneficial in conditions where dyslipidemia occurs by lowering serum cholesterol levels, also have been proposed for use in neurodegenerative conditions, including Alzheimer disease. However, it is not clear that the purported effectiveness of statins in neurodegenerative disorders is directly related to cholesterol-lowering effects of these agents; rather, the pleiotropic functions of statins likely play critical roles. Moreover, it is becoming more apparent with additional studies that statins can have deleterious effects in preclinical studies and lack effectiveness in various recent clinical trials. This perspective paper outlines pros and cons of the use of statins in neurodegenerative disorders, with particular emphasis on Alzheimer disease.

Topics: Alzheimer Disease; Animals; Atorvastatin; Cholesterol; Fatty Acids, Monounsaturated; Fluorobenzenes; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Neurodegenerative Diseases; Pyrimidines; Pyrroles; Quinolines; Rosuvastatin Calcium; Sulfonamides

Structural and functional abnormalities in the neurovascular unit (NVU) have been recently observed in Alzheimer's disease (AD). Statins, which are used clinically for reducing cholesterol levels, can also exert beneficial vascular actions. Thus, we examined the protective effects of statins on NVU disturbances in a mouse AD model. Amyloid precursor protein (APP) transgenic (Tg) mice were used as a model of AD. Atorvastatin (30 mg/kg/day, p.o.) or pitavastatin (3 mg/kg/day, p.o.) were administered from 5 to 20 months of age. Changes in the NVU, including the endothelium and basement membrane, as well as astrogliosis and matrix metalloproteinase-9 (MMP-9) activation, were assessed. There was a reduction in immunopositive staining for N-acetyl glucosamine oligomer (NAGO) in the endothelium and in collagen IV in the APP vehicle (APP/Ve) group, with collagen IV staining most weakest near senile plaques (SPs). There was also an increase in intensity and number of glial fibrillary acidic protein (GFAP)-positive astrocytes, particularly around the SP, where MMP-9 was more strongly labeled. Double immunofluorescent analysis showed that astrocytic endfeet had detached from the capillary endothelium in the APP/Ve group. Treatment with atorvastatin or pitavastatin ameliorated the activation of MMP-9. Overall, these data suggest that statins may have therapeutic potential for AD by protecting NVU.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Atorvastatin; Blotting, Western; Cerebral Cortex; Cerebrovascular Circulation; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Female; Fluorescent Antibody Technique; Heptanoic Acids; Humans; Immunohistochemistry; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Neuroprotective Agents; Pyrroles; Quinolines

Present study was designed to investigate modulation of experimental dementia by Pitavastatin and donepezil. Learning and memory of the swiss albino mice were studied on Morris water-maze. Celecoxib orally (p.o.)/Streptozotocin (STZ) intracerebroventricular administrations were used to induce experimental dementia. Brain acetyl cholinesterase activity was measured by EllMann's method to assess cholinergic activity of the brain. Brain thio barbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively, to assess total oxidative stress in brain. Total serum cholesterol level was measured by Allain's method. Celecoxib/STZ treatments produced a significant loss of learning and memory. Pitavastatin/Donepezil successfully attenuated this Celecoxib/STZ induced dementia. Higher levels of brain acetyl-cholinesterase (AChE) activity, TBARS and lower level of GSH were observed in Celecoxib/STZ treated animals, which were significantly attenuated by Donepezil. Pitavastatin also attenuated the Celecoxib/STZ induced high levels of TBARS & low levels of GSH without effecting AChE activity and total serum cholesterol levels. Celecoxib induced dementia noted in the present study may be attributed to its stimulatory effect on amyloid beta-42, brain AChE activity, and oxidative stress. Sub-diabetogenic STZ induced memory deficits closely related to Alzheimer's disease. Reversal of Celecoxib/STZ induced memory deficits by Pitavastatin may be due to its antioxidative, anti beta amyloid aggregatory property, and by Donepezil, due to its anticholinesterase and neuroprotective actions.

Topics: Acetylcholinesterase; Administration, Oral; Alzheimer Disease; Animals; Brain; Celecoxib; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drug Therapy, Combination; Escape Reaction; Female; Glutathione; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indans; Injections, Intraventricular; Male; Maze Learning; Mental Recall; Mice; Nootropic Agents; Piperidines; Pyrazoles; Quinolines; Streptozocin; Sulfonamides; Thiobarbituric Acid Reactive Substances