Amyloid-b precursor protein (APP) is the source of the amyloid-beta (Ab) peptide found in neuritic plaques of Alzheimer’s disease (AD) patients. APP is a glycosylated transmembrane protein with a long extracellular N-terminal domain, a short intracellular C-terminal domain, and an Ab-segment of intermediate length shared between the intra- and extracellular regions.1 APP is cleaved by a-secretase immediately before or after reaching the cell surface, releasing the non-amyloidogenic secreted form of the N-terminal soluble APP fragment (sAPPa).2 APP molecules that are not cleaved by a-secretase are internalized, and subjected to b-site cleavage by b-secretase, leaving behind a membrane-bound C-terminal stub.3 This terminal stub is the substrate for g-secretase, which cleaves the molecule at g-site(s) to release the 40 aa, 42 aa, or 43 aa’long Ab peptides.4 Processing of APP by b- and g-secretases occurs under normal physiological conditions, indicating that all fragments of APP, including Ab, play roles in normal physiology.4-5 In neurons, around 95% of APP is cleaved by g-secretases while 5% is cleaved by b-secretase.6 Excessive generation of Ab and its subsequent oligomerization and fibrillation leads to the detrimental effects of AD. Reductions in the level or activity of certain APP fragments, in addition to accumulation of Ab, may play a critical role in the cognitive dysfunction associated with AD, especially in the early stages of the disease. APP fragments including Ab regulate key neural functions including cell excitability, synaptic transmission, long-term potentiation, behavorial learning, and memory.7