Extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) are hallmark of Alzheimer disease (AD). These aggregates, along with actin-containing inclusions due to abnormalities of actin cytoskeleton induced by amyloid ? (A?), lead to axonal transport defect and thereby, axon degeneration. Vasodilator-stimulated phosphoprotein (VASP) is a processive actin polymerase and its abnormal activation mediates the formation of actin inclusions under pathological condition. TRIM9 brain-specific ubiquitin ligase ubiquitinates and degrades VASP to facilitate axon branching during neural development, suggesting that TRIM9 is a critical brain- specific E3 ubiquitin ligase that controls VASP-mediated axon branch formation and NF-?B- mediated neuroinflammation in normal conditions. As a hyperactive VASP mediates A? aggregate- induced actin inclusion formation and thereby contributes to axon degeneration in AD patients, we hypothesize that TRIM9 E3 ubiquitin ligase interacts with and degrades the hyperactive VASP to inhibit axon degeneration, thereby alleviating AD pathogenesis. To test this hypothesis, we propose to utilize in vitro biochemical approach (Aim 1) and in vivo mouse model (Aim 2). Collectively, this supplemental proposal provides a unique way to extend our understanding role of TRIM9 ubiquitin ligase in AD progression and facilitates the development of therapeutic approach.
Extracellular amyloid ? (A?) plaques and intracellular neurofibrillary tangles (NFTs) are hallmark of Alzheimer disease (AD). The abnormal activation of Vasodilator-stimulated phosphoprotein (VASP) is a processive actin polymerase. As a hyperactive VASP mediates A? aggregate-induced actin inclusion formation and thereby contributes to axon degeneration in AD patients, we hypothesize that TRIM9 E3 ubiquitin ligase interacts with and degrades the hyperactive VASP to inhibit axon degeneration, thereby alleviating AD pathogenesis.
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