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.
Although the causal factor for Alzheimer's disease (AD) remains to be determined, human genetic and epidemiological studies support the hypothesis that abnormal accumulation of amyloid peptides (A?), which are the major component in plaques, leads to the formation of A? oligomers and subsequent formation of amyloid plaques. A? is generated from a large membrane-anchored protein called amyloid precursor protein (APP). APP needs to be first cleaved by BACE1 at the ?-secretase site and further cleavage of the BACE1-released APP C-terminal fragment by ?-secretase will release A?. Increased formation of senile amyloid plaques leads to a cascade of events that includes neuroinflammation and neuronal loss, as well as synaptic impairments. Therefore, inhibition of BACE1 activity could reduce or even prevent A? generation to avoid excessive amyloid deposition, so it is an important and widely-pursued strategy for AD therapy. Currently, five compounds are being tested in clinical trials for AD patients. This study aims to provide therapeutic guidance by testing how BACE1 inhibition can be safe and effective. Our approach is to use a BACE1 conditional deletion mouse model in which BACE1 activity can be ablated at various adult stages. We will also explore how pre-existing amyloid plaques are removed when BACE1 activity is inhibited. Obtaining this knowledge is highly important as it will provide timely guidance for the safe and effective use of BACE1 inhibitors in human patients.
