Targeting γ-secretase for familial Alzheimer's disease

Familial Alzheimer's disease (FAD) is a rare early-onset genetic form of 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 beta-secretase and gamma-secretase to produce the amyloid beta-peptide (A beta). Presenilin is the catalytic component of gamma-secretase, a membrane-embedded aspartyl protease complex that cleaves APP within its single transmembrane domain to produce A beta of varying lengths. Thus, all FAD mutations are found in the substrate and the enzyme that produce A beta. The 42-residue variant A beta 42 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 A beta and A beta 42 have failed in the clinic, including gamma-secretase inhibitors, leading to questioning of the amyloid hypothesis of Alzheimer pathogenesis. However, processing of the APP transmembrane domain by gamma-secretase is complex, involving initial endoproteolysis followed by successive carboxypeptidase trimming steps to secreted A beta peptides such as A beta 42. Recent findings reveal that FAD mutations in PSEN1 and in APP result in the deficient trimming of initially formed long A beta 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.

Automated summary

Familial Alzheimer's disease (FAD) is a rare genetic form of early-onset dementia caused by missense mutations in three genes related to Aβ and Aβ42. While treatments targeting Aβ and Aβ42 have been unsuccessful, recent findings suggest that FAD mutations play a key role in the deficient trimming of Aβ peptides, indicating a potential focus for future drug development.