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APP, short for Amyloid Precursor Protein, is a transmembrane glycoprotein. It is best-known for its association with Alzheimer's disease (AD) as the precursor from which amyloid-β (Aβ) peptides are generated through proteolytic cleavage [2,5]. APP also has diverse physiological functions in the human adult brain, such as intracellular signaling, synaptic and neuronal plasticity, and cell adhesion [2]. It contributes to the regulation of synaptic transmission, plasticity, and calcium homeostasis, and exerts neuroprotective effects [1].

Analysis of APP-mutant mice, including knockout (KO) models, has provided insights into its role. APP deletion in mice leads to major dysregulation within the presynaptic active zone (PAZ) proteome network, affecting Ca2 +-homeostasis, neurotransmitter release, and mitochondrial function, which resemble outcomes during AD pathogenesis, suggesting APP is a structural and functional regulator within the hippocampal PAZ proteome [3]. Both overexpression and KO of APP in mice lead to impaired synaptic plasticity, indicating its importance in this process [4].

In conclusion, APP plays essential roles in normal brain physiology, especially in synaptic function and plasticity. The study of APP-KO mouse models has been crucial in revealing its role in AD-related pathophysiological processes, highlighting its significance in understanding the disease mechanism and potentially developing new therapeutic strategies for Alzheimer's disease.