Targeting γ-Secretase for Familial Alzheimer's Disease

Familial Alzheimer's disease (FAD) is a rare early-onset genetic form of a common dementia of old age. Striking in middle age, FAD is caused by missense mutations in three genes: APP (encoding the amyloid precursor protein) and PSEN1 and PSEN2 (encoding presenilin-1 and presenilin-2). APP is proteolytically processed successively by β-secretase and γ-secretase to produce the amyloid β-peptide (Aβ). Presenilin is the catalytic component of γ-secretase, a membrane-embedded aspartyl protease complex that cleaves APP within its single transmembrane domain to produce Aβ of varying lengths. Thus, all FAD mutations are found in the substrate and the enzyme that produce Aβ. The 42-residue variant Aβ42 has been the primary focus of Alzheimer drug discovery for over two decades, as this particular peptide is highly prone to aggregation, is the major protein deposited in the characteristic cerebral plaques of Alzheimer's disease, and is proportionately elevated in FAD. Despite extensive efforts, all agents targeting Aβ and Aβ42 have failed in the clinic, including γ-secretase inhibitors, leading to questioning of the amyloid hypothesis of Alzheimer pathogenesis. However, processing of the APP transmembrane domain by γ-secretase is complex, involving initial endoproteolysis followed by successive carboxypeptidase trimming steps to secreted Aβ peptides such as Aβ42. Recent findings reveal that FAD mutations in PSEN1 and in APP result in deficient trimming of initially formed long Aβ peptides. A logical drug discovery strategy for FAD could therefore involve the search for compounds that rescue this deficient carboxypeptidase activity. The rare early-onset FAD arguably presents a simpler path to developing effective therapeutics compared to the much more complex heterogeneous sporadic Alzheimer's disease.