Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in Alzheimer's disease.

Lindsay H Burns,Hoau-Yan Wang

doi:10.20517/2347-8659.2017.50

Lindsay H Burns, Hoau-Yan Wang

Open Access

https://doi.org/10.20517/2347-8659.2017.50

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease with proteopathy characterized by abnormalities in amyloid beta (Aβ) 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 Aβ and required for two prominent pathogenic signaling pathways of Aβ. Aβ monomers or small oligomers signal via the α7 nicotinic acetylcholine receptor (α7nAChR) 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 Aβ, leading to excessive inflammatory cytokine release and neuroinflammation. The novel AD therapeutic candidate PTI-125 binds and reverses the altered FLNA conformation to prevent Aβ’s signaling via α7nAChR and aberrant activation of TLR4, thus reducing multiple AD-related neuropathologies. As a regulator of Aβ’s signaling via α7nAChR and TLR4, altered FLNA represents a novel AD therapeutic target.

Highlights

Alzheimer’s disease (AD) is a complex neurodegenerative disease characterized by a variety of synaptic and receptor dysfunctions, neuroinflammation, insulin resistance, degeneration and atrophy
We suggest that the signaling of Aβ42 via α7 nicotinic acetylcholine receptor (α7nAChR) contributes prominently to a variety of AD-related neuropathologies in addition to, or perhaps elicited by, tau hyperphosphorylation because these additional neuropathologies are reduced by PTI-125’s disruption of Aβ42’s signaling via α7nAChR[13,15]
Abnormal filamin A (FLNA) is intertwined with the Aβ and tau proteopathies in AD

Summary

INTRODUCTION

Alzheimer’s disease (AD) is a complex neurodegenerative disease characterized by a variety of synaptic and receptor dysfunctions, neuroinflammation, insulin resistance, degeneration and atrophy. This third proteopathy is an altered conformation of the scaffolding protein FLNA It is induced by Aβ42, and in reciprocal action, enables Aβ42’s toxic signaling via α7nAChR to activate kinases that hyperphosphorylate tau[13]. Prevention of the FLNA linkage to α7nAChR by FLNA-binding compound PTI125 decreases Aβ42’s affinity for this receptor 1,00010,000-fold, illustrating that FLNA enables Aβ42’s toxic signaling and its high-affinity binding for α7nAChR[15] This observation appears to suggest that altered FLNA is responsible for Aβ42’s binding, we propose a dynamic, sequential process: (1) Aβ42 binds α7nAChR to induce FLNA recruitment; (2) recruitment alters FLNA’s conformation; and (3) FLNA’s altered form secures (locks in) an ultra-high affinity Aβ42-α7nAChR interaction. As with α7nAChR, native FLNA in control brains does not associate with TLR4, unless treated with Aβ42 by ICV infusion to wildtype mice or by in vitro incubation of Altered filamin A enables Aβ signaling to propagate dysfunction in AD brains. We speculate that altered FLNA may alter actin dynamics, given the primary role of FLNA in the actin cytoskeleton

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