γ-Secretase and its modulators: Twenty years and beyond

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Presenilin protein's active site in gamma-secretase identified 20 years ago.
• Mutations in amyloid precursor protein (APP) or presenilin (PS) genes cause early-onset familial Alzheimer's disease (AD).
• Sequential cleavage of APP by beta-secretase and gamma-secretase generates amyloid beta (Aβ), a key component of neuritic plaques in AD brains.

Purpose of the Study:

• To review studies on gamma-secretase and its inhibitors/modulators since presenilin's discovery.
• To analyze reasons for clinical trial failures and identify lessons learned.
• To explore new therapeutic directions for AD targeting gamma-secretase modulators.

Main Methods:

• Review of scientific literature on gamma-secretase, presenilin, and Alzheimer's disease therapeutics.
• Analysis of clinical trial data for gamma-secretase inhibitors and modulators.
• Discussion of the role of gamma-secretase modulators in neuroinflammation and tau pathology.

Main Results:

• Targeting gamma-secretase/presenilin to reduce amyloid has been a focus of therapeutic strategies, leading to clinical trials.
• A lack of complete understanding of presenilin biology contributed to clinical trial failures.
• Lessons from gamma-secretase modulators, though premature for human testing, offer new therapeutic avenues.

Conclusions:

• Imbalanced Aβ homeostasis is an upstream event in neurodegenerative processes.
• Exploring gamma-secretase modulators is significant for decreasing neuroinflammation and phosphorylated tau levels.
• Agents with favorable human pharmacology show promise for suppressing neurodegeneration in early-stage AD patients.