APP, the Amyloid Precursor Protein, is a transmembrane glycoprotein infamous for its proposed role in Alzheimer's disease (AD) pathogenesis as the source of amyloid-β (Aβ) peptides. However, it also has essential physiological functions. APP contributes to synaptic transmission, plasticity, calcium homeostasis, and exerts neuroprotective effects. It plays a role in cell-adhesion, intracellular signaling, and is involved in synapse formation and stability [1].

Analysis of APP-mutant mice, including gene knockout (KO) models, has provided insights. In APP-mutant mice, the hippocampal presynaptic active zone (PAZ) proteome is dysregulated, affecting Ca2+-homeostasis, neurotransmitter release, and mitochondrial function, similar to AD pathogenesis, suggesting APP is a structural and functional regulator within the hippocampal PAZ proteome [1]. Both APP overexpression and knockout in mice lead to impaired synaptic plasticity, indicating its importance in this process [2].

In conclusion, APP is crucial for normal brain physiology, with functions in synaptic and neuronal plasticity, cell adhesion, and calcium signaling. The study of APP-KO mouse models has been instrumental in understanding its role in AD, highlighting its dysregulation as a key factor in the disease's pathogenesis. This research provides a basis for developing new pathophysiological concepts and therapeutic approaches for AD [1].

References:

1. Weingarten, Jens, Weingarten, Melanie, Wegner, Martin, Volknandt, Walter. 2017. APP-A Novel Player within the Presynaptic Active Zone Proteome. In Frontiers in molecular neuroscience, 10, 43. doi:10.3389/fnmol.2017.00043. https://pubmed.ncbi.nlm.nih.gov/28265241/

2. Montagna, Elena, Dorostkar, Mario M, Herms, Jochen. 2017. The Role of APP in Structural Spine Plasticity. In Frontiers in molecular neuroscience, 10, 136. doi:10.3389/fnmol.2017.00136. https://pubmed.ncbi.nlm.nih.gov/28539872/