The Role of Tau in Alzheimer's Disease and Related Disorders

Medeiros, Rodrigo; Baglietto‐Vargas, David; LaFerla, Frank M.

doi:10.1111/j.1755-5949.2010.00177.x

Cited by 245 publications

(188 citation statements)

References 119 publications

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“…Multiple lines of evidence suggest that tau hyperphosphorylation results from perturbation of cellular signaling, mainly through an imbalance in the activities of different PKs and phosphatases. 27 Herein, we show that M 1 R specifically modulates the tau phosphorylation through the regulation of GSK3␤ activity. The increase in tau phosphorylation was selective because we found an increase in phosphorylated tau only at GSK3␤-targeted residues after the deletion of M 1 R in the 3xTgAD mice [ie, S202/T205 (detected by antibody AT8), T181 (detected by antibody AT270), and T212/ S214 (detected by antibody AT100)].…”

Section: Discussionmentioning

confidence: 99%

“…tau is regulated during both normal homeostasis and stress-induced responses by an array of post-translational modifications, including phosphorylation, a process regulated by various PKs and phosphatases. 27 No differences in the activation of tau kinase CDK5, evaluated by analyzing levels of p35 and p25, and in the levels of the major tau phosphatase, PP2A, were found between 3xTgAD-M 1 R Ϫ/Ϫ and 3xTgAD mice (Figure 4, D and E). On the other hand, a significant increase in the activation of tau kinase GSK3␤ was found in the animals lacking the M 1 R. GSK3␤ activation is negatively regulated by phosphorylation at S9.…”

Section: Ablating the M 1 R Gene Accelerates Tau Pathological Featuresmentioning

confidence: 99%

See 1 more Smart Citation

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Medeiros

Kitazawa

Caccamo

et al. 2011

The American Journal of Pathology

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106

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Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and ␤-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M 1 receptors (M 1 Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M 1 Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M 1 R ؊/؊ mice. Our data show that M 1 R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M 1 R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar A␤ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1 R were attributed to changes in the glycogen synthase kinase 3␤ and protein kinase C activities. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive impairment and dementia. The neuropathological hallmarks of AD are amyloid plaques, composed of ␤-amyloid (A␤) peptides, and neurofibrillary tangles, composed of the hyperphosphorylated tau protein. The deposition of fibrillar A␤ in the cerebrovasculature, a condition known as cerebral amyloid angiopathy (CAA), is also a prominent feature of AD. Together with associated processes, such as inflammation and oxidative stress, these pathological cascades contribute to loss of synaptic integrity and progressive neurodegeneration. 1Restoring cholinergic dysfunction has been a primary means of improving the cognitive decline in AD because four of the five Food and Drug Administration-approved drugs are acetylcholinesterase inhibitors, with the notable exception of memantine.2 Acetylcholinesterase inhibitors provide mild symptomatic relief but eventually lose efficacy over time, most likely because they are not disease-modifying agents.1 Alternatively, recent evidence 3,4 indicates that stimulation of muscarinic acetylcholine receptors, in particular the M 1 receptor (M 1 R), restores cognition and attenuates AD-like pathological features in several different animal models, rendering it an attractive therapeutic approach for AD. The M 1 R is the most abundant muscarinic acetylcholine receptor subtype in the cerebral cortex and hippocampus, the two main brain reSupported by grants from the NIH (NIH/NIAMS K99AR054695 to M.K.; NIH/NIA R01AG20335 and Program Project AG00538 to F.M.L.).

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Section: Discussionmentioning

confidence: 99%

Section: Ablating the M 1 R Gene Accelerates Tau Pathological Featuresmentioning

confidence: 99%

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Medeiros

Kitazawa

Caccamo

et al. 2011

The American Journal of Pathology

Self Cite

106

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“…The phosphorylation of tau protein, which mainly mediated by microtubule-associated regulatory kinase (MARK), cyclin-dependent kinase-5 (CDK5), and glycogen synthase kinase 3β (GSK-3β), increases dramatically in AD patients [82,83], showing that the inhibitors of tau kinases could have the ability of anti-AD. Valproate (VPA) showed its inhibitory effects on tau hyperphosphorylation in both AD transgenic mice and SH-SY5Y cell model, which might be realized through both regulating GSK3β and CDK5 signalling pathways [84].…”

Section: Prevention Of Tau Phosphorylationmentioning

confidence: 99%

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

Li¹,

Zhou²,

Wu³

et al. 2015

ADMET DMPK

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“…Hyperphosphorylated tau translocates from the axons and dendrites where it stabilizes microtubules, to somal and nuclear compartments. In these intracellular spaces, tau aggregates and forms abnormal tangles of paired-helical filaments (PHFs) that can be observed histologically (Medeiros et al, 2011). PHF-tau is a reliable marker of neurofibrillary tangles (NFTs) and correlates with dementia severity of AD patients (Bierer et al, 1995).…”

Section: Alzheimer's Disease Pathologymentioning

confidence: 99%

“…The net result of loss of ACh signalling has been addressed through loss of function studies, where deletion of muscarinic ACh receptors in transgenic AD mice resulted in an exacerbation of cognitive impairment. However it also resulted in an increase in plaque and tangle levels, and changes in glycogen synthase kinase-3β (GSK3β) and protein kinase C activity (Medeiros, 2011;Davis, 2010). Along with the expected consequences of reduced ACh on memory mechanisms, such as changes in synaptic plasticity and consolidation in the hippocampus, impaired cholinergic function also directly regulates AD-related signalling mechanisms.…”

Section: Cholinergic Hypofunction In Alzheimer's Diseasementioning

confidence: 99%

Neurotrophin regulation of Alzheimer's disease pathology

Turnbull¹

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Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized histopathologically by the accumulation of amyloid-β (Aβ) and hyperphosphorylation of tau protein. These two key proteins are major contributors to neuronal toxicity and disease progression; however, the causal factors initiating this toxic cascade in sporadic disease are unknown. We hypothesize that the specific degeneration of basal forebrain cholinergic neurons (BFCNs) and a decrease in neurotrophin availability -which occur coincidentally with the disease -are key regulators of aberrant Aβ accumulation and tau hyperphosphorylation, and could constitute the molecular basis of AD pathology in sporadic disease. Here we show that loss of BFCN innervation to the hippocampus of two pre-symptomatic mouse lines modelling the disease (APP/PS1 and pR5 (P301L) mice) causes a reduction in hippocampal and nerve growth factor (NGF) protein and/or brain-derived neurotrophic factor (BDNF). In APP/PS1 mice this correlates with memory and learning deficits in a Morris water maze task, which is not observed in unlesioned transgenic controls and wildtype littermates -indicating an exacerbation of the disease. Loss of BFCN hippocampal innervation in APP/PS1 mice also increases the amount of total Aβ in the hippocampus, but has no additional effects on levels of tau hyperphosphorylation. In contrast, memory deficits are not observed in pR5 tau transgenic mice following an equivalent loss of BFCN hippocampal innervation and reduction of neurotrophin levels. Moreover, hippocampal levels of tau and hyperphosphorylated tau were comparable to that of control pR5 tau transgenic mice. The role of neurotrophins in Aβ pathology in APP/PS1 mice was further assessed through viral knockdown of BDNF protein in the hippocampus, and treatment with a neurotrophic c29 peptide following loss of basal forebrain cholinergic neurons. Although reduction of BDNF did not cause increased Aβ levels, and treatment with c29 peptide did not reduce Aβ load in the hippocampus of APP/PS1 mice following loss of BFCN, c29 peptide was able to rescue behavioural deficits of aged unlesioned APP/PS1 mice.This work demonstrates that early cholinergic denervation of the hippocampus can trigger some features of Alzheimer's disease, namely reduced neurotrophin expression and increased Aβ production, but does not alone cause tau hyperphosphorylation and aggregation. These results are consistent with the idea that tau pathology in AD may be downstream of Aβ pathology, and highlights the possibility that cholinergic dysfunction might be a major upstream contributing factor of sporadic Alzheimer's disease. Although we show that neurotrophin dysfunction is insufficient by itself to induce or prevent Aβ accumulation, enhancing neurotrophic signalling to provide cognitive benefit may be a viable treatment strategy.

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The Role of Tau in Alzheimer's Disease and Related Disorders

Cited by 245 publications

References 119 publications

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

Neurotrophin regulation of Alzheimer's disease pathology

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