Inhibition of BACE1 for benefiting Alzheimer's patients

University Of Connecticut Sch Of Med/Dnt, Farmington CT

Investigators

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Abstract

ABSTRACT Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by the presence of amyloid plaques and neurofibrillary tangles. Although it remains highly contested, the ?Amyloid Cascade Hypothesis? is still gaining support from both human and mouse studies that suggest an imbalance between the production and clearance of A? as an early or often initiating factor in AD pathogenesis. For AD therapy, decreasing A? generation or enhancing A? clearance is being actively pursued. A? is generated from amyloid precursor protein (APP) through two sequential proteolytic cleavages by BACE1 and ?-secretase. Inhibition of BACE1 is expected to block the formation of A?, thereby reducing amyloid deposition in AD patients. Five BACE1 inhibitors are currently in Phase II/III clinical trials thanks to breakthrough progress in developing central nervous system (CNS)-penetrable BACE1 inhibitors. While results from these trials are eagerly anticipated, one such trial was surprisingly terminated in early 2017. This setback will no doubt raise questions as to whether BACE1 inhibitors should still proceed in clinical trials. While pharmaceutical companies are testing these compounds in humans, we aims to answer the question as to whether controlled inhibition of BACE1 activity in the adult will have ultimate effects on reducing or reversing AD pathologies by using BACE1 conditional knockout (KO) mice. We found that deletion of BACE1 in 5xFAD mice at early adult stages is sufficient to remove pre-existing amyloid plaques. However, many important questions remain to be answered. For example, it is not understood as to how pre-existing plaques can be removed and how BACE1 inhibition plays a role in removing these existing amyloid plaques. It is also not yet clear as to whether significant inhibition or deletion of BACE1 at later adult stages will have similar effects on removing existing amyloid plaques, and this question is most relevant to BACE1 inhibitory drugs that are likely to be given to elderly patients. In this study, we aim to test our hypothesis that BACE1 inhibition will not only reduce generation of ?-amyloid peptides, but will also enhance clearance of ?-amyloid peptides. Our two specific aims are: 1) To determine whether deletion of BACE1 in older adult mice reverses pre-formed amyloid plaques in AD transgenic mouse brains; and 2) To investigate how pre-formed amyloid plaques are removed after BACE1 deletion. We postulate that BACE1 inhibition enhances phagocytic functions in microglia by efficiently removing amyloid plaques, and we have obtained preliminary results to support this hypothesis.