Amyloid precursor protein
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Amyloid Precursor Protein: Functions, Processing, and Implications
Introduction to Amyloid Precursor Protein (APP)
Amyloid precursor protein (APP) is a transmembrane glycoprotein that plays a crucial role in the pathogenesis of Alzheimer's disease (AD) through its cleavage into amyloid-β (Aβ) peptides, which aggregate to form plaques in the brain 12. However, APP's physiological functions extend beyond its involvement in AD, encompassing various roles in neural development, synaptic function, and metabolic processes 134.
APP in Neural Development and Synaptic Function
APP and its homologs, amyloid precursor-like proteins (APLP1 and APLP2), are essential for central nervous system (CNS) development and synapse formation. Studies using knockout mice have demonstrated that APP family members are involved in neurogenesis, neurite outgrowth, axonal guidance, and synaptogenesis 138. Protein-protein interactions involving APP are critical for these processes, and disruptions in these interactions can lead to neurodevelopmental defects and contribute to neurodegenerative diseases .
APP Trafficking and Proteolytic Processing
The intracellular trafficking and proteolytic processing of APP are central to its function and the generation of Aβ peptides. APP can be processed via two main pathways: the amyloidogenic pathway, which produces Aβ peptides, and the non-amyloidogenic pathway, which precludes Aβ formation 26. The amyloidogenic pathway involves sequential cleavage by β-secretase and γ-secretase, while the non-amyloidogenic pathway involves α-secretase cleavage within the Aβ domain 26. Recent studies have identified a third processing pathway involving concerted cleavages by α- and β-secretase, leading to shorter Aβ isoforms .
APP in Metabolic Diseases
Beyond its role in the CNS, APP is expressed in peripheral tissues, including the liver, pancreas, adipose tissue, and myotubes. APP peptides generated by non-amyloidogenic processing positively influence metabolism, whereas those produced by amyloidogenic processing have adverse effects . Abnormal APP expression and function are associated with metabolic diseases such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, cardiovascular disease, and certain cancers 47. Targeting APP function or reducing amyloidogenic peptide production may offer therapeutic strategies for both AD and metabolic diseases .
APP in Vascular Endothelium
APP is also expressed in the endothelial cells of cerebral and peripheral arteries, where it plays roles in vascular health. The mechanisms of APP expression and cleavage in endothelial cells have implications for both physiological and pathological conditions, including vascular diseases .
Therapeutic Implications and Future Directions
Understanding the diverse roles of APP in neural development, synaptic function, metabolism, and vascular health is crucial for developing effective therapies for AD and other related conditions. Investigating APP's physiological functions and its interactions with other proteins can provide insights into novel therapeutic targets and strategies 138. Additionally, the development of substrate-specific inhibitors for γ-secretase could potentially mitigate the production of pathogenic Aβ peptides without affecting other essential functions of APP .
Conclusion
Amyloid precursor protein (APP) is a multifaceted protein with significant roles in neural development, synaptic function, metabolism, and vascular health. While its involvement in Alzheimer's disease pathogenesis is well-documented, ongoing research continues to uncover its broader physiological functions and potential therapeutic targets. Understanding these diverse roles is essential for developing comprehensive treatment strategies for AD and other related diseases.
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