A Novel Treatment Approach in Alzheimer’s Disease: sAPPα (original) (raw)

Alzheimer's disease (AD) is the most common cause of age-related dementia and the number of patients with AD is increasing worldwide. The amyloid cascade hypothesis(ACH) provides a fundamental perspective for the pathogenesis of AD. It is also strongly criticized due to the failure of the clinical trials that experimented with anti-amyloid drugs. Dar et al. brilliantly pointed out that sAPPα could be developed as a novel therapeutic agent in treatment of AD(1). In the ACH model amyloid precursor protein(APP) is cleaved either by β-secretase followed by γ-secretase(amyloidogenic pathway) or α-secretase followed by γ-secretase(nonamyloidogenic pathway). It is the amyloidogenic pathway that ACH mostly focuses on as many studies showed the neurotoxic effects of β-amyloid. However, there is growing evidence showing non-amyloidogenic pathway products have essential roles in several significant physiological processes including neurite growth, learning and memory, neural progenitor cell proliferation, and neural survival(2,3,4,5). Studies by Small et al. and Allinqu ant et al. demonstrate that sAPPα promotes neurite outgrowth(6,7). sAPPα also plays a role in synaptogenesis(8). Zheng et al. showed that APP KO mice display neurological deficits that can be explained by effects on synaptogenesis(9). Zou et al. found that sAPPα is important in maintaining constitutive and adaptive plasticity of dendritic spines in the adult brain(10). sAPPα also demonstrates neuroprotective properties(11). Obregon et al. demonstrated that sAPPα decreases βamyloid by modulating APP processing via BACE1(12). The study showed that while blocking sAPPα increases Aβ production, overexpression of sAPPα decreases amyloid plaques and soluble Aβ. sAPPα also stimulates the proliferation of embryonic neural stem cells(NSCs)(13,14). Studies by Caillé et al. showed that infusion of APP antisense oligonucleotides reduces prolif