Complexity and Selectivity of γ -Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer

Alessandro Medoro, Silvia Bartollino, Donatella Mignogna, Daniela Passarella, Carola Porcile, Aldo Pagano, Tullio Florio, Mario Nizzari, Germano Guerra, Roberto Di Marco, Mariano Intrieri, Gennaro Raimo, Claudio Russo

Research output: Contribution to journalReview article

Abstract

The processing of the amyloid-β protein precursor (AβPP) by β- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AβPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration. This theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin's "gain of function" versus "loss of function"; and 2) the presence of several and various GS substrates, which interact with AβPP and may influence Aβ formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AβPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AβPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AβPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer.

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalJournal of Alzheimer's Disease
Volume61
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

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Keywords

  • Alzheimer's disease
  • AβPP
  • cancer
  • cell migration
  • LDL receptor
  • Notch
  • β-secretase
  • γ-secretase

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Medoro, A., Bartollino, S., Mignogna, D., Passarella, D., Porcile, C., Pagano, A., Florio, T., Nizzari, M., Guerra, G., Di Marco, R., Intrieri, M., Raimo, G., & Russo, C. (2018). Complexity and Selectivity of γ -Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer. Journal of Alzheimer's Disease, 61(1), 1-15. https://doi.org/10.3233/JAD-170628