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Current Alzheimer Research
ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
VOLUME: 3
ISSUE: 5
DOI: 10.2174/156720506779025242      Price:  $58









Pathways by Which Aβ Facilitates Tau Pathology

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Author(s): Mathew Blurton-Jones and Frank M. LaFerla
Pages 437-448 (12)
Abstract:
Since the initial description one hundred years ago by Dr. Alois Alzheimer, the disorder that bears his name has been characterized by the occurrence of two brain lesions: amyloid plaques and neurofibrillary tangles (NFTs). Yet the precise relationship between beta-amyloid (Aβ) and tau, the two proteins that accumulate within these lesions, has proven elusive. Today, a growing body of work supports the notion that Aβ may directly or indirectly interact with tau to accelerate NFT formation. Here we review recent evidence that Aβ can adversely affect distinct molecular and cellular pathways, thereby facilitating tau phosphorylation, aggregation, mis-localization, and accumulation. Studies are presented that support four putative mechanisms by which Aβ may facilitate the development of tau pathology. A great deal of work suggests that Aβ may drive tau pathology by activating specific kinases, providing a straightforward mechanism by which Aβ may enhance tau hyperphosphorylation and NFT formation. In the AD brain, Aβ also triggers a massive inflammatory response and pro-inflammatory cytokines can in turn indirectly modulate tau phosphorylation. Mounting evidence also suggests that Aβ may inhibit tau degradation via the proteasome. Lastly, Aβ and tau may indirectly interact at the level of axonal transport and evidence is presented for two possible scenarios by which axonal transport deficits may play a role. We propose that the four putative mechanisms described in this review likely mediate the interactions between Aβ and tau, thereby leading to the development of AD neurodegeneration.
Keywords:
Phosphorylation, inflammation, proteasome, axonal transport, neurofibrillary tangles, PHF, oligomer, amyloid
Affiliation:
Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Bldg., Irvine, CA 92697-4545, USA.