Dataset Information

Co-occurrence of Alzheimer's disease ß-amyloid and ? pathologies at synapses.

ABSTRACT: Although beta-amyloid (Abeta) plaques and tau neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) neuropathology, loss of synapses is considered the best correlate of cognitive decline in AD, rather than plaques or tangles. How pathological Abeta and tau aggregation relate to each other and to alterations in synapses remains unclear. Since aberrant tau phosphorylation occurs in amyloid precursor protein (APP) Swedish mutant transgenic mice, and since neurofibrillary tangles develop in triple transgenic mice harboring mutations in APP, tau and presenilin 1, we utilized these well-characterized mouse models to explore the relation between Abeta and tau pathologies. We now report that pathological accumulation of Abeta and hyperphosphorylation of tau develop concomitantly within synaptic terminals.

SUBMITTER: Takahashi RH

PROVIDER: S-EPMC2909664 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Co-occurrence of Alzheimer's disease ß-amyloid and τ pathologies at synapses.

Takahashi Reisuke H RH Capetillo-Zarate Estibaliz E Lin Michael T MT Milner Teresa A TA Gouras Gunnar K GK

Neurobiology of aging 20080903 7

Although beta-amyloid (Abeta) plaques and tau neurofibrillary tangles are hallmarks of Alzheimer's disease (AD) neuropathology, loss of synapses is considered the best correlate of cognitive decline in AD, rather than plaques or tangles. How pathological Abeta and tau aggregation relate to each other and to alterations in synapses remains unclear. Since aberrant tau phosphorylation occurs in amyloid precursor protein (APP) Swedish mutant transgenic mice, and since neurofibrillary tangles develop ...[more]

PMID: 18771816

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Project description:Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (P2Y12R). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and AppNL-F/NL-F mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.

Dataset Information

Co-occurrence of Alzheimer's disease ß-amyloid and ? pathologies at synapses.

Publications

Co-occurrence of Alzheimer's disease ß-amyloid and τ pathologies at synapses.

Similar Datasets

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