The processing of the amyloid-Î² protein precursor (AÎ²PP) by Î²- and Î³-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AÎ²PP 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 Î³-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AÎ²PP by GS induces the formation of specific neurotoxic soluble amyloid-Î² (AÎ²) 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 AÎ²PP and may influence AÎ² formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AÎ²PP 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 AÎ²PP 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 AÎ²PP 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.
|Digital Object Identifier (DOI):||http://dx.doi.org/10.3233/JAD-170628|
|Codice identificativo ISI:||WOS:000416369700001|
|Codice identificativo Scopus:||2-s2.0-85036513435|
|Titolo:||Complexity and Selectivity of Î³ -Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer|
|Appare nelle tipologie:||1.1 Articolo in rivista|