M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing …


  1. Claes Wahlestedta,b,1

  1. aCenter for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136;

  2. bDepartment of Psychiatry, Miller School of Medicine, University of Miami, Miami, FL 33136;

  3. cDepartment of Molecular Medicine, Scripps Florida, Jupiter, FL 33458
  1. Edited by Li-Huei Tsai, Massachusetts Institute of Technology, Cambridge, MA, and accepted by Editorial Board Member Susan
    G. Amara September 2, 2017 (received for review May 8, 2017)

Significance

Hundreds of failed clinical trials with Alzheimer’s disease (AD) patients over the last fifteen years demonstrate that the
one-target–one-disease approach is not effective in AD. In silico, structure-based, multitarget drug design approaches to
treat multifactorial diseases have not been successful in the context of AD either. Here, we show that M344, an inhibitor
of class I and IIB histone deacetylases, affects multiple AD-related genes, including those related to both early- and late-onset
AD. We also show that M344 improves memory in the 3xTg AD mouse model. This work endorses a shift to a multitargeted approach
to the treatment of AD, supporting the therapeutic potential of a single small molecule with an epigenetic mechanism of action.

Abstract

Alzheimer’s disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to
broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate
multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single
drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule
histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEε4 gene expression. M344 increases the expression of AD-relevant
genes: BDNF, α-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, and ABCA7, among others. M344 increases sAPPα and CTFα
APP metabolite production, both cleavage products of ADAM10, concordant with increased ADAM10 gene expression. M344 also increases
levels of immature APP, supporting an effect on APP trafficking, concurrent with the observed increase in MINT2 and FE65,
both shown to increase immature APP in the early secretory pathway. Chronic i.p. treatment of the triple transgenic (APPsw/PS1M146V/TauP301L) mice with M344, at doses as low as 3 mg/kg, significantly prevented cognitive decline evaluated by Y-maze spontaneous alternation,
novel object recognition, and Barnes maze spatial memory tests. M344 displays short brain exposure, indicating that brief
pulses of daily drug treatment may be sufficient for long-term efficacy. Together, these data show that M344 normalizes several
disparate pathogenic pathways related to AD. M344 therefore serves as an example of how a multitargeting compound could be
used to address the polygenic nature of multifactorial diseases.

Footnotes

  • Author contributions: C.-H.V., H.S.-U., K.J.J., P.H., and C.W. designed research; C.-H.V., H.S.-U., K.J.J., P.H., G.L., A.W.,
    S.M., N.H.P., G.C.S., N.M., N.T.H.M., S.D., D.D., and M.D.C. performed research; C.-H.V., H.S.-U., K.J.J., P.H., G.L., A.W.,
    S.M., N.H.P., G.C.S., N.M., M.D.C., S.P.B., and C.W. analyzed data; C.-H.V. and C.W. wrote the paper; C.-H.V., H.S.-U., P.H.,
    and C.W. conceived of the project; and S.P.B. and C.W. provided financial support.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. L.-H.T. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1707544114/-/DCSupplemental.

Freely available online through the PNAS open access option.



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