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Burns et al. Altered filamin A enables Aβ signaling

First, the alteration in FLNA has not been directly those using postmortem human AD or Aβ 42 -treated
demonstrated. It is implied by a shift in pI for FLNA in control brainwith postmortem interval < 10 h. PTI-125
AD vs. control brain and supported by the differential demonstrated efficacy in postmortem human brain at
binding affinities of PTI-125 to FLNA in control vs. AD concentrations as low as 1 pmol/L [13] .
brain. Representing an aggregate pKa for all amino
acids in a protein, a shifted pI is assumed to reflect CONCLUSION
a change in structure. Second, the possibility exists
that PTI-125 has additional significant targets besides Abnormal FLNA is intertwined with the Aβ and
FLNA’s altered conformation that have confounded our tau proteopathies in AD. Aβ 42 induces the altered
interpretation of its effects. We believe this is a remote conformation of FLNA, and altered FLNA enables
possibility because: (1) PTI-125 showed no interactions sustained Aβ 42 signaling via α7nAChR and TLR4,
in a lead profiling screen of 68 receptors, channels possibly by securing high affinity binding of Aβ [13,15] .
and transporters; (2) the binding affinity of PTI-125 in Aβ 42 ’s toxic signaling via α7nAChR activates kinases to
AD brain was virtually identical to its binding affinity for hyperphosphorylate tau [25-31] , leading to its dysfunction
FLNA immunopurified from AD brain [13] , indicating a and aggregation, and the FLNA-enabled Aβ 42
lack of other CNS targets; and (3) PTI-125 shows good activation of TLR4 enhances neuroinflammation [13,15] .
CNS penetration and more than sufficient brain levels Moreover, the altered conformation of FLNA is an
for a femtomolar target. important catalyst of Aβ toxicities and tau dysfunction,
including neuroinflammation and synaptic dysfunction.
Both Aβ and tau as AD therapeutic targets have been The novel therapeutic candidate PTI-125 offers the
questioned following multiple clinical trial failures, and possibility of dampening these toxic cascades by
this skepticism may extend to altered FLNA as a viable restoring the native conformation of FLNA. In addition
therapeutic target for AD. Furthermore, several partial to its novel target, preferentially binding and reversing
agonists or positive allosteric modulators to α7nAChR an altered protein conformation is a novel mechanism
have also failed, challenging the significance of this of action for any drug candidate. An advantage
Aβ signaling pathway. As commonly suggested, of its mechanism is that PTI-125 dramatically
potential reasons for these failures include treating too attenuates Aβ’s aberrant activation of both α7nAChR
late in disease progression, because neuropathology and TLR4 without directly affecting these surface
precedes symptoms by 10-25 years [58,59] , and the receptors. PTI-125 preserves tau’s neuronal function,
possible protective effect of amyloid [60] . Additionally, preserving axonal transport, and reduces Aβ-induced
agents that target aggregation of Aβ or tau may be neuroinflammation and synaptic/dendritic damage
downstream of significant dysfunction, as suggested while maintaining health of the receptors. AD is a
by the pathways discussed here. Perhaps most disease of multiple dysfunctions. Interconnected with
importantly, the femtomolar interaction of Aβ 42 several toxicities of Aβ and tau and implicated in
with α7nAChR imposes substantial competition for
antibodies or small molecules seeking to compete many AD-related neuropathologies, the proteopathy
directly with this interaction. of FLNA represents an entirely new target for AD drug
development.
An additional caution to interpretation of our data
may be our use of synthetic, monomeric Aβ 42 rather DECLARATIONS
than oligomeric Aβ, thought to be the most toxic
Aβ species. Though transgenic mice generate both Authors’ contributions
monomeric and oligomeric Aβ, Aβ 42 in vitro forms a Wrote the manuscript: L.H. Burns
mixture of monomers and small oligomers as well, and Performed all experimental studies on PTI-125 and
both signal via α7nAChR [51] . edited the manuscript: H.Y. Wang
Finally, despite the broad spectrum of beneficial effects Financial support and sponsorship
demonstrated preclinically by PTI-125’s reversal The PTI-125 program was supported by NIH grants
of FLNA’s altered conformation, Aβ 42 signaling via AG050301 and AG056166 (LHB), and a plasma-
α7nAChR and TLR4 are only two of many pathogenic based companion diagnostic/biomarker is supported
cascades in AD. A variety of other approaches have by NIH grant AG057329 (GBT).
demonstrated similar results in mouse models, and the
difficulty of clinical translation remains. We believe our Conflicts of interest
strongest data validating FLNA’s altered conformation LHB is an employee of and HYW is a consultant to
as a novel target for AD drug development are Pain Therapeutics Inc., who owns all rights to PTI-125
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ December 8, 2017 269