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J Neurosci. 2010 Oct 6;30(40):13409-18. doi: 10.1523/JNEUROSCI.1964-10.2010.

Convergence of presenilin- and tau-mediated pathways on axonal trafficking and neuronal function.

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  • 1Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA.


Alzheimer's disease (AD) is a significant and growing health problem in the aging population. Although definitive mechanisms of pathogenesis remain elusive, genetic and histological clues have implicated the proteins presenilin (PS) and tau as key players in AD development. PS mutations lead to familial AD, and although tau is not mutated in AD, tau pathology is a hallmark of the disease. Axonal transport deficits are a common feature of several neurodegenerative disorders and may represent a point of intersection of PS and tau function. To investigate the contribution of wild-type, as opposed to mutant, tau to axonal transport defects in the context of presenilin loss, we used a mouse model postnatally deficient for PS (PS cDKO) and expressing wild-type human tau (WtTau). The resulting PS cDKO;WtTau mice exhibited early tau pathology and axonal transport deficits that preceded development of these phenotypes in WtTau or PS cDKO mice. These deficits were associated with reduced neurotrophin signaling, defective learning and memory and impaired synaptic plasticity. The combination of these effects accelerated neurodegeneration in PS cDKO;WtTau mice. Our results strongly support a convergent role for PS and tau in axonal transport and neuronal survival and function and implicate their misregulation as a contributor to AD pathogenesis.

[PubMed - indexed for MEDLINE]
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