BACE1 in neurodegeneration and neurological dysfunction

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Abstract Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disease with progressive impairment in synaptic and cognitive functions occurred early in the disease course. For past three decades, various hypotheses are proposed to determine the cause of AD pathogenesis. The amyloid hypothesis is being tested most extensively in the field because of strong supports from human genetic and epidemiological studies. The main essence of hypothesis is that the abnormal level of β- amyloid peptide (Aβ) leads to sequential pathological developments that eventually cause a potential of synaptic and cognitive dysfunctions in AD patients. Consistently, deletion or inhibition of BACE1, which is a sole enzyme for cleaving amyloid precursor protein (APP) at the β-secretase site to initiate the generation of Aβ, reduces Aβ production and amyloid pathology. Brain penetrable inhibitors are tested in clinical trials but fail to improve cognitive functions in AD patients, resulting in the early termination of clinical trials. We and others show that BACE1 regulates synaptic plasticity and clinical used BACE1 inhibitors actually impair synaptic function at a clinically tested dose. In this proposal, we aim to find solutions that will take the advantage of this plaque reduction and can overcome the unwanted side effects associated with worsening cognitive functions/scores. Our goal is to develop strategy that improve synaptic functions in association with BACE1 inhibition in AD patients. We will test our central hypothesis that BACE1 inhibitors will be more effective for AD treatment if BACE1-mediated synaptic impairment is under controls. Two specific aims are proposed to test our hypothesis: Aim 1 is to differentiate toxic Aβ-mediated and BACE1-mediated synaptic impairments in mouse models. Aim 2 is to determine whether mGluR1 positive allosteric modulator will improve AD and BACE1-mediated synaptic impairment. The ultimate goal is to optimize the use of BACE1 inhibitors and supplement with synaptic enhancer such as a positive allosteric modulator (PAM) of metabotropic glutamate receptor-1 (mGluR1) in AD mice. Our preliminary studies support shows improved long term potentiation in BACE1-null mice treated with an mGluR1 PAM. Knowledge gained from this study will guide the future clinical application of BACE1 in human.