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Burns et al. Altered filamin A enables Aβ signaling

ultimately form the histopathological hallmarks of AD described proteopathy is an altered conformation of
brain: amyloid plaques and tau-containing tangles. the ubiquitous scaffolding protein filamin A (FLNA),
Misfolded dysfunctional proteins and their aggregation induced by Aβ 42 and without apparent aggregation [13] .
occurs in many other neurodegenerative diseases The 1st toxic cascade of Aβ enabled by altered
including Parkinson’s disease, dementia with Lewy FLNA is Aβ’s signaling via α7 nicotinic acetylcholine
bodies, multiple systems atrophy, frontotemporal receptor (α7nAChR) to hyperphosphorylate tau. The
dementia, amyotrophic lateral sclerosis and 2nd signaling pathway is Aβ’s aberrant activation of
Huntington’s disease [1-4] . Typically, misfolded proteins toll-like-receptor 4 (TLR4), by binding CD14 [14] , to
self-aggregate, creating intracellular inclusions that induce neuroinflammation. In both cases, altered
become extracellular deposits following cell death. In FLNA associates with these receptors to allow their
many cases, misfolded proteins propagate in a cell-to- aberrant signaling by Aβ [13,15] . Native FLNA in control
cell “prion-like” manner [1-3,5] . brains does not associate with either receptor.
Whether the altered conformation precedes or is a
The proteopathy of Aβ in AD is an amyloidosis, consequence of these receptor linkages is discussed.
meaning the protein converts from an α-helix-rich The interdependence of altered FLNA with Aβ
state to a β-sheet conformation. To enter an amyloid signaling to hyperphosphorylate tau and promote
or β-sheet state, proteins must expose the backbone neuroinflammation has been elucidated via the
amide N-H and C=O groups to allow hydrogen reversal of the FLNA proteopathy by a small molecule
[4]
bonding . Cleavage of amyloid precursor protein into therapeutic candidate, PTI-125.
Aβ 42 by secretases can expose these amide N-H and
[4]
C=O groups and promote a β-sheet conformation . Aβ SIGNALING VIA α7NACHR TO
Elevated concentrations from overproduction or HYPERPHOSPHORYLATE TAU
insufficient clearance/processing may also contribute.
The hydrogen bonding of the pleated, β-sheet The most toxic form of Aβ is considered soluble Aβ
conformation between parallel or anti-parallel β-sheets oligomers rather than plaque deposits [16,17] . Evidence
is much stronger than that in native α-helices, making that soluble Aβ induces tau pathology has grown, with
reversal unlikely. Additionally, the β-sheet conformation hyperphosphorylation as the primary pathological
allows hydrogen bonding between separate, stacked modification [18] . Extensive research has elucidated
molecules, promoting oligomerization and eventual the role of the α7nAChR in the toxicity of soluble Aβ 42
[4]
plaque formation . Aβ is proposed to form a toxic, and the consequent hyperphosphorylation of tau [19-24] .
small oligomer “seed” requiring 3 or 4 molecules Soluble Aβ 42 in monomeric or oligomeric form binds
used as a template to “infect” native molecules and and signals via α7nAChR [25-28] , essentially hijacking this
propagate in a prion-like manner . receptor to abnormally activate various kinases [27,29-31]
[6]
to heighten tau phosphorylation. Supportive data
The proteopathy of tau, or tauopathy, in AD is primarily include co-localization of Aβ 42 and α7nAChR in AD
caused by hyperphosphorylation. Hyperphosphorylated pyramidal neurons and a complete blockade of Aβ 42 -
tau loses its function of stabilizing microtubules and induced tau hyperphosphorylation in vitro by α7nAChR
[7]
dissociates from them . The increased pool of free antisense oligonucleotides [32] . Aβ 42 dose-dependently
tau after dissociation from microtubules is likely an activates tau kinases to persistently phosphorylate tau
[8]
important first step to aggregation in AD . Untethered at the three proline-directed sites, resulting in elevated
from microtubules, hyperphosphorylated tau twists hyperphosphorylated tau in neurofibrillary tangles.
together to form the paired helical filaments (PHFs) This Aβ-driven tau hyperphosphorylation can also be
found in neurofibrillary tangles. In a toxic gain of blocked by the α7nAChR antagonist α-bungarotoxin
function, hyperphosphorylated tau also actively disrupts or other α7nAChR ligands if administered
microtubules and inhibits their assembly [7,9] and even prophylactically [32-35] . The hyperphosphorylation of tau
sequesters functional tau and other microtubule renders it dysfunctional, alters its cellular distribution
[9]
associated proteins . Hyperphosphorylation also and disrupts axonal/dendritic transport, leading to
changes tau’s localization from axon-predominant to neurofibrillary lesions, dendritic breakdown, and
include dendrites, neuronal cell bodies and presynaptic ultimately, neurofibrillary tangles [27] . Importantly,
areas, leading to synaptic dsyfunction [10-12] . soluble Aβ 42 binds α7nAChR with an extraordinarily
high (high femtomolar) affinity, rendering the Aβ 42 -
This mini-review focuses on a third, interconnected α7nAChR interaction nearly irreversible [26,36] .
proteopathy in AD and its critical role in 2 toxic
signaling pathways of soluble Aβ. The newly Though other targets have been demonstrated for

264 Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ December 8, 2017