piperidines and Tauopathies

Alzheimer's disease (AD) is the most common cause of dementia, which affects more than 5 million individuals in the USA. Unfortunately, no effective therapies are currently available to prevent development of AD or to halt progression of the disease. It has been proposed that monoacylglycerol lipase (MAGL), the key enzyme degrading the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, is a therapeutic target for AD based on the studies using the APP transgenic models of AD. While inhibition of 2-AG metabolism mitigates β-amyloid (Aβ) neuropathology, it is still not clear whether inactivation of MAGL alleviates tauopathies as accumulation and deposition of intracellular hyperphosphorylated tau protein are the neuropathological hallmark of AD. Here we show that JZL184, a potent MAGL inhibitor, significantly reduced proinflammatory cytokines, astrogliosis, phosphorylated GSK3β and tau, cleaved caspase-3, and phosphorylated NF-kB while it elevated PPARγ in P301S/PS19 mice, a tau mouse model of AD. Importantly, tau transgenic mice treated with JZL184 displayed improvements in spatial learning and memory retention. In addition, inactivation of MAGL ameliorates deteriorations in expression of synaptic proteins in P301S/PS19 mice. Our results provide further evidence that MAGL is a promising therapeutic target for AD.

Topics: Alzheimer Disease; Animals; Arachidonic Acids; Benzodioxoles; Cognition; Endocannabinoids; Female; Glycerides; Inflammation Mediators; Male; Maze Learning; Mice; Mice, Transgenic; Monoacylglycerol Lipases; Piperidines; tau Proteins; Tauopathies

Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell-derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.

Topics: Animals; Brain; Disease Models, Animal; Enzyme Inhibitors; Farnesyltranstransferase; Female; GTP-Binding Proteins; Humans; Induced Pluripotent Stem Cells; Lysosomes; Male; Mice; Mice, Transgenic; Mutation; Neurons; Piperidines; Proteolysis; Pyridines; RNA, Small Interfering; tau Proteins; Tauopathies; Translational Research, Biomedical

Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19). Eight months of DZ treatment resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, and neuronal loss, as well as decreased tau insolubility and phosphorylation. Tau kinase activity analysis demonstrated significantly suppressed c-Jun N-terminal kinase (JNK) in the brains of DZ-treated PS19 mice. Recently, ACh has been shown to suppress inflammation, which plays a role in neurodegeneration. To confirm the anti-inflammatory effect of DZ, PS19 mice were injected with lipopolysaccharide, in combination with or without DZ, for one month. Results demonstrated that DZ suppressed IL-1β and COX-2 expression in the brain, as well as the spleen, suggesting that DZ directly prevents systemic inflammation. These data indicated that ACh did not act just as a cognition-linking neurotransmitter, but might suppress pathological mechanisms of neurodegeneration via anti-inflammatory action.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Donepezil; Humans; Indans; Mice; Mice, Inbred C3H; Mice, Transgenic; Mutation; Nerve Degeneration; Piperidines; Synapses; tau Proteins; Tauopathies

Cholinesterase inhibitors (ChEIs) are effective symptomatic treatments in dementia with Lewy bodies (DLB), although effects on pathologic mechanisms are unknown. In the first human autopsy study examining the impact of ChEI treatment on brain pathology, we compared treated patients with DLB with matched untreated patients for cortical beta-amyloid (Abeta) and tau pathologies. Treated patients with DLB had significantly less parenchymal Abeta deposition, which is relevant to disease management and treatment of dementia patients using ChEI.

Topics: Aged; Aged, 80 and over; Amyloid beta-Peptides; Autopsy; Cerebral Cortex; Cholinesterase Inhibitors; Clinical Trials as Topic; Cohort Studies; Donepezil; Drug Evaluation; Female; Galantamine; Humans; Indans; Lewy Body Disease; Male; Middle Aged; Neuroprotective Agents; Phenylcarbamates; Piperidines; Prospective Studies; Rivastigmine; Tacrine; tau Proteins; Tauopathies