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The role of tau in Alzheimer's disease and related disorders.

ABSTRACT: Tau, the microtubule-associated protein, forms insoluble filaments that accumulate as neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. Under physiological conditions, tau regulates the assembly and maintenance of the structural stability of microtubules. In the diseased brain, however, tau becomes abnormally hyperphosphorylated, which ultimately causes the microtubules to disassemble, and the free tau molecules aggregate into paired helical filaments. A large body of evidence suggests that tau hyperphosphorylation results from perturbation of cellular signaling, mainly through imbalance in the activities of different protein kinases and phosphatases. In AD, it appears that ß-amyloid peptide (Aß) plays a pivotal role in triggering this imbalance. In this review, we summarize our current understanding of the role of tau in AD and other tauopathies, and highlight key issues that need to be addressed to improve the success of developing novel therapies.

SUBMITTER: Medeiros R

PROVIDER: S-EPMC4072215 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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The role of tau in Alzheimer's disease and related disorders.

Medeiros Rodrigo R Baglietto-Vargas David D LaFerla Frank M FM

CNS neuroscience & therapeutics 20100614 5

Tau, the microtubule-associated protein, forms insoluble filaments that accumulate as neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. Under physiological conditions, tau regulates the assembly and maintenance of the structural stability of microtubules. In the diseased brain, however, tau becomes abnormally hyperphosphorylated, which ultimately causes the microtubules to disassemble, and the free tau molecules aggregate into paired helical filaments. A large body of ...[more]

PMID: 20553310

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Project description:BackgroundChanges in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-β (Aβ) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum.MethodsWe included 533 individuals (178 Aβ-negative cognitively unimpaired (CU) subjects, 105 Aβ-positive CU subjects, 122 Aβ-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions.ResultsAcross the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aβ-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology.ConclusionsOur data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.

Dataset Information

The role of tau in Alzheimer's disease and related disorders.

Publications

The role of tau in Alzheimer's disease and related disorders.

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