Regulated intramembrane proteolysis, innate immunity and therapeutic targets in Alzheimer’s disease

The critical discovery of the presenilins and their association with familial Alzheimer’s disease (AD) prompted an intensive research effort to understand the molecular mechanisms of that disease. The presenilins were subsequently found to be the catalytic component of the multi-protein enzyme complex, γ-secretase, the enzyme that is known to act on the amyloid precursor protein (APP) to generate amyloid beta (Aβ) peptides that comprise the neuritic plaques implicated in AD pathology. Here, we discuss the background of γ-secretase- mediated proteolysis of APP and its association with familial AD. We discuss the association of neuroinflammation with AD, focusing on the link between the innate immune response, the clearance of the Aβ peptides and disease progression. Currently, there are limited treatments for AD that strive to ameliorate the symptoms of the disease but do not address the molecular basis of the disease. The greater understanding of γ- secretase functions has provided new insights into potential therapeutics for AD, a number of which are in clinical trials.