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

The processing of the amyloid-beta protein precursor (A beta PP) by beta- and gamma-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the A beta PP 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 gamma-secretase (GS). The amyloid hypothesis, modified over time, states that the aberrant processing of A beta PP by GS induces the formation of specific neurotoxic soluble amyloid-beta (A beta) 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 A beta PP and may influence A beta formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with A beta PP 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 A beta PP 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 A beta PP 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.