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

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. Key words:Proteopathy, hyperphosphorylation, α7 nicotinic acetylcholine receptor, toll-like receptor 4, neuroinflammation, PTI-125 ABSTRACTArticle history:

S-nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy

“…Our results correlate with previous findings showing accumulation and increased levels of NFAT isoforms in post-mortem brains from patients with AD, which further suggest that changes in NFAT levels contribute to AD progression; 62 The fact that they found increase of NFAT in both early and late stage of the disease suggests that our early molecular findings are linked to the later disease mechanism as well. Other recent studies also showed an increase of NFAT-1 in a different transgenic AD mouse model 63 , and a third proteopathy for AD, suggests that an alteration of the scaffolding protein FILAMIN-A, is critically linked to the amyloid and tau pathologies in AD and leads to increased tau phosphorylation 64 . Another study showed that FILAMIN-A inhibitors decrease P-Tau and amyloid-beta aggregates 65 .…”

Influenza A Virus Nucleoprotein Activates the JNK Stress-Signaling Pathway for Viral Replication by Sequestering Host Filamin A Protein

“…Filamin A has been reported to interact with more than 90 functionally diverse range of cellular proteins, including adhesion proteins, transmembrane receptors, transcription proteins, and signaling molecules, thus making it a key component of the host cell signaling scaffold (Savoy and Ghosh, 2013;Wang et al, 2015;Burns and Wang, 2017). In general, high-throughput virus-host interactomes revealed that viral proteins show preferential interaction with proteins having high number of direct interacting partners; making FLNA an interesting target of study (Dyer et al, 2008;Komarova et al, 2011;Munier et al, 2013;de Chassey et al, 2014).…”

Cerebrospinal fluid biomarkers for cognitive disorders. An introductory overview

“…The former process mobilizes various mechanisms that are toxic to neurons [26] , and the second results in destabilization of microtubules and dysfunction of the cytoskeleton and of axonal transport [27] . Both processes, acting synergistically, lead to neuritic, synaptic and neuronal loss, through a vicious circle of interconnecting final pathways of oxidative stress, excitotoxicity, mitochondrial dysfunction, apoptosis and Ca 2+ -mediated cell death [28][29][30] , while prion-like spread [31] and neuroinflammation [32][33][34] are increasingly recognized as important early mechanisms.…”