Abstract
Alzheimer’s disease (AD) is an intractable, neurodegenerative disease that appears to be brought about by both genetic and non-genetic factors. The neuropathology associated with AD is complex, although amyloid plaques composed of the β-amyloid peptide (Aβ) are hallmark neuropathological lesions of AD brain. Indeed, Aβ plays an early and central role in this disease. β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the initiating enzyme in Aβ genesis and BACE1 levels are elevated under a variety of conditions. Given the strong correlation between Aβ and AD, and the elevation of BACE1 in this disease, this enzyme is a prime drug target for inhibiting Aβ production in AD. However, nine years on from the initial identification of BACE1, and despite intense research, a number of key questions regarding BACE1 remain unanswered. Indeed, drug discovery and development for AD continues to be challenging. While current AD therapies temporarily slow cognitive decline, treatments that address the underlying pathologic mechanisms of AD are completely lacking. Here we review the basic biology of BACE1. We pay special attention to recent research that has provided some answers to questions such as those involving the identification of novel BACE1 substrates, the potential causes of BACE1 elevation and the putative function of BACE1 in health and disease. Our increasing understanding of BACE1 biology should aid the development of compounds that interfere with BACE1 expression and activity and may lead to the generation of novel therapeutics for AD.
Highlights
Several major pathological abnormalities characterize Alzheimer’s disease (AD), including the A-containing extracellular amyloid plaques, intracellular neurofibrillary tangles, neuroinflammation, neuronal dysfunction and neuron death
We demonstrated that memory deficits and cholinergic dysfunction in the hippocampus did not develop in BACE1-/-Tg2576 bigenic mice that lacked A, while florid deficits were apparent in A-overproducing Tg2576 monogenics
To address whether the BACE1 elevation observed in AD brain is merely a passive end product of advanced neurodegeneration and cell death or whether it is actively involved in disease progression, we examined BACE1 levels in two Tg models of AD [143], namely the 5XFAD mouse [60] that develops amyloid plaques at young ages and exhibits significant neuronal loss, and the Tg2576 mouse [52], which develops plaques at older ages and does not show neuronal death
Summary
Several major pathological abnormalities characterize AD, including the A-containing extracellular amyloid plaques, intracellular neurofibrillary tangles, neuroinflammation, neuronal dysfunction and neuron death. The apolipoprotein (Apo) E4 allele on chromosome 19, is a strong risk factor for LOAD [5] and is associated with atherosclerosis. There is a close relationship between AD and cardiovascular disease with coronary artery disease, hypertension and hypercholesterolemia, amongst others, being significant AD risk factors [6,7,8,9,10]. How such risk factors impact AD risk and the putative molecular mechanisms underlying this association are the current focus of intense investigation. Strategies to lower A42 levels in the brain are anticipated to be of therapeutic benefit in AD
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