Affiliations: [a] Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| [b] Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| [c] Department of Brain Sciences, Imperial College London, London, United Kingdom
| [d] Shanxi Medical University, Taiyuan, People’s Republic of China
Correspondence:
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Correspondence to: Kah-Leong Lim, Ph.D., Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232. E-mail: [email protected].
Abstract: Alzheimer’s disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia.
Keywords: Alzheimer’s disease, amyloid-β protein precursor secretase, beta-secretase, neuroprotection
