Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease.
Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease.
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DOI：
10.20517/2347-8659.2017.50
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Wang, Hoau-Yan
中科院分区：
文献类型：
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作者：
Burns, Lindsay H;Wang, Hoau-Yan
Alzheimer's disease (AD) is a neurodegenerative disease with proteopathy characterized by abnormalities in amyloid beta (Abeta) and tau proteins. Defective amyloid and tau propagate and aggregate, leading to eventual amyloid plaques and neurofibrillary tangles. New data show that a third proteopathy, an altered conformation of the scaffolding protein filamin A (FLNA), is critically linked to the amyloid and tau pathologies in AD. Altered FLNA is pervasive in AD brain and without apparent aggregation. In a striking interdependence, altered FLNA is both induced by Abeta and required for two prominent pathogenic signaling pathways of Abeta. Abeta monomers or small oligomers signal via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) to activate kinases that hyperphosphorylate tau to cause neurofibrillary lesions and formation of neurofibrillary tangles. Altered FLNA also enables a persistent activation of toll-like-receptor 4 (TLR4) by Abeta, leading to excessive inflammatory cytokine release and neuroinflammation. The novel AD therapeutic candidate PTI-125 binds and reverses the altered FLNA conformation to prevent Abeta's signaling via alpha7nAChR and aberrant activation of TLR4, thus reducing multiple AD-related neuropathologies. As a regulator of Abeta's signaling via alpha7nAChR and TLR4, altered FLNA represents a novel AD therapeutic target.
