The Normal and Pathologic Roles of the Alzheimer's β-secretase, BACE1

Abstract

As the most common neurodegenerative disease, therapeutic avenues for the treatment and prevention of Alzheimer's Disease are highly sought after. The aspartic protease BACE1 is the initiator enzyme for the formation of Aβ, a major constituent of amyloid plaques that represent one of the hallmark pathological features of this disorder. Thus, targeting BACE1 for disease-modifying AD therapies represents a rationale approach. The collective knowledge acquired from investigations of BACE1 deletion mutants and characterization of BACE1 substrates has downstream significance not only for the discovery of AD drug therapies but also for predicting side effects of BACE1 inhibition. Here we discuss the identification and validation of BACE1 as the β-secretase implicated in AD, in addition to information regarding BACE1 cell biology, localization, substrates and potential physiological functions derived from BACE1 knockout models.

Cross-Sectional and Longitudinal Effects of CREB1 Genotypes on Individual Differences in Memory and Executive Function: Findings from the BLSA

“…One potentially important interaction partner for CREB appears to be BACE1, which besides cleaving APP may also regulate synaptic plasticity and myelination (Kandalepas and Vassar, 2014). Upregulation of BACE1 protein level has been reported to downregulate the cAMP-PKA-CREB signaling pathway independent of BACE1 activity for Aβ generation (Chen et al, 2012).…”

The emerging role of alternative splicing in senescence and aging

“…Among age‐related disorders, AD is characterized by progressive neurodegenerative phenotypes leading to memory loss and dementia (Burns & Iliffe, ), possibly caused by aggregation of amyloid beta (Aβ) in the brain (Zheng & Koo, ; Kandalepas & Vassar, ). Aβ is the product of two subsequent enzymatic digestions driven, respectively, by the β‐secretase (BACE) and the γ‐secretase; the initial substrate for these enzymes is the amyloid precursor protein (APP) (Citron et al ., ; Koffie et al ., ; Zheng & Koo, ; Chami & Checler, ; Kandalepas & Vassar, ). BACE turns out to be a more desirable target against AD as γ‐secretase is believed to be more critical for normal function (Mowrer & Wolfe, ).…”

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Additionally, a7 nAChR stimulation could potentially play a role in rescuing presynaptic deficits in AD as a result of decreasing levels of b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) (Vassar et al, 2009;Kandalepas and Vassar, 2014;Yan and Vassar, 2014). In 2010, an intriguing study examined the connection between activation of a7 nAChRs in BACE1 knockout mice, showing restoration of pairpulsed facilitation from mossy fiber-to-CA3 synapses, which is reflective of deficits in presynaptic release (Wang et al, 2010a).…”