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Burns et al. Neuroimmunol Neuroinflammation 2017;4:263-71 Neuroimmunology and
DOI: 10.20517/2347-8659.2017.50
Neuroinflammation

www.nnjournal.net
Topic: Alzheimer’s Disease Open Access

Altered filamin A enables amyloid beta-

induced tau hyperphosphorylation and

neuroinflammation in Alzheimer’s disease

Lindsay H. Burns , Hoau-Yan Wang 2,3
1
1 Pain Therapeutics Inc., Austin, TX 78731, USA.
2 Department of Physiology, Pharmacology and Neuroscience, City University of New York School of Medicine, New York, NY 10031, USA.
3 Department of Biology and Neuroscience, Graduate School of the City University of New York, New York, NY 10031, USA.
Correspondence to: Dr. Lindsay H. Burns, Pain Therapeutics Inc., 7801 N. Capital of Texas Hwy, Ste. 260, Austin, TX 78731, USA.
E-mail: lburns@paintrials.com
How to cite this article: Burns LH, Wang HY. Altered filamin A enables amyloid beta-induced tau hyperphosphorylation and neuroinflammation in
Alzheimer’s disease. Neuroimmunol Neuroinflammation 2017;4:263-71.

ABSTRACT
Article history: Alzheimer’s disease (AD) is a neurodegenerative disease with proteopathy characterized by
Received: 25 Sep 2017 abnormalities in amyloid beta (Aβ) and tau proteins. Defective amyloid and tau propagate and
First Decision: 16 Oct 2017 aggregate, leading to eventual amyloid plaques and neurofibrillary tangles. New data show
Revised: 20 Oct 2017 that a third proteopathy, an altered conformation of the scaffolding protein filamin A (FLNA),
Accepted: 8 Nov 2017 is critically linked to the amyloid and tau pathologies in AD. Altered FLNA is pervasive in
Published: 8 Dec 2017 AD brain and without apparent aggregation. In a striking interdependence, altered FLNA
Key words: is both induced by Aβ and required for two prominent pathogenic signaling pathways of
Proteopathy, Aβ. Aβ monomers or small oligomers signal via the α7 nicotinic acetylcholine receptor
hyperphosphorylation, (α7nAChR) to activate kinases that hyperphosphorylate tau to cause neurofibrillary lesions
α7 nicotinic acetylcholine and formation of neurofibrillary tangles. Altered FLNA also enables a persistent activation
receptor, of toll-like-receptor 4 (TLR4) by Aβ, leading to excessive inflammatory cytokine release
toll-like receptor 4, and neuroinflammation. The novel AD therapeutic candidate PTI-125 binds and reverses the
neuroinflammation, altered FLNA conformation to prevent Aβ’s signaling via α7nAChR and aberrant activation of
PTI-125 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.

INTRODUCTION and atrophy. Although the pathogenesis of AD is
debated, the disease itself can be considered a
A l zh e i m e r ’s d i s e as e ( A D) i s a c o m p l e x proteopathy, a disease of abnormal proteins, due to
neurodegenerative disease characterized by a the misfolding and aggregation of amyloid beta (Aβ)
variety of synaptic and receptor dysfunctions, and hyperphosphorylated tau in brain areas critical
neuroinflammation, insulin resistance, degeneration to cognition and memory. These abnormal proteins

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