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Amyloid Precursor Protein (APP): Trafficking, Processing, and Physiological Functions
Introduction to Amyloid Precursor Protein (APP)
Amyloid precursor protein (APP) is a type 1 transmembrane glycoprotein that plays a crucial role in the pathogenesis of Alzheimer's disease (AD) through its processing into amyloid-β (Aβ) peptides. These peptides are central to the formation of amyloid plaques, a hallmark of AD1 7. However, APP and its homologs, amyloid precursor-like proteins (APLPs), also have significant physiological roles in neuronal homeostasis, development, and synaptic function2 4.
APP Trafficking and Processing
Endosomal and Trans-Golgi Network (TGN) Pathways
APP is processed through a complex intracellular trafficking system involving endosomes and the trans-Golgi network (TGN). APP is initially trafficked from the cell surface to early endosomes. From there, it can either be recycled back to the TGN or proceed through the multivesicular body pathway1. The retromer complex, particularly VPS35, is essential for recycling APP from early endosomes to the TGN, which is crucial for efficient Aβ40 production1. Disruption in this trafficking can lead to the accumulation of APP in early endosomes, reducing its processing and subsequent Aβ production1.
Secretase-Mediated Cleavage
APP undergoes sequential cleavage by β-site APP cleaving enzyme (BACE1) and γ-secretase to produce Aβ peptides. This amyloidogenic pathway is contrasted by the non-amyloidogenic pathway, where α-secretase cleaves APP within the Aβ sequence, preventing Aβ formation and releasing a neuroprotective fragment known as secreted APP-alpha (APPsα)5 9. APPsα has been shown to have neurotrophic and neuroprotective properties, making it a potential therapeutic target for AD and other neurodegenerative conditions5.
Isoforms and Functional Implications
APP Isoforms and AICD Production
APP exists in several isoforms, including APP695, APP751, and APP770, which arise from alternative splicing. Among these, APP695 is particularly significant in neurons and is preferentially processed to produce the APP intracellular domain (AICD) via β-secretase activity3. AICD plays a role in gene regulation, including the upregulation of neprilysin (NEP), an enzyme that degrades Aβ3. This isoform-specific processing underscores the importance of APP695 in neuronal function and Aβ regulation.
Novel Splice Variants
Recent studies have identified novel splice variants of APP, such as those lacking exon 15, which are expressed in leukocytes and brain microglial cells. These variants may influence APP processing and Aβ production, potentially contributing to the pathogenesis of AD6.
Physiological Functions Beyond Alzheimer's Disease
Role in CNS Development and Synaptic Function
Beyond its role in AD, APP and APLPs are involved in central nervous system (CNS) development, synapse formation, and function. Knockout studies in mice have revealed that APP family members are crucial for these processes, highlighting their broader physiological significance2.
APP in Cancer
Interestingly, APP and APLPs are also expressed in non-neuronal tissues and have been implicated in cancer. Overexpression of these proteins in cancer cells suggests a role in tumorigenesis, although the exact mechanisms remain to be fully elucidated4.
Conclusion
Amyloid precursor protein (APP) is a multifaceted protein with significant roles in both the pathogenesis of Alzheimer's disease and normal physiological processes. Its trafficking and processing are tightly regulated, involving complex intracellular pathways and secretase-mediated cleavage. Understanding these mechanisms not only provides insights into AD but also reveals potential therapeutic targets for a range of neurological and non-neurological conditions. Further research into APP's diverse functions and isoforms will continue to uncover its full biological significance.
Sources and full results
Most relevant research papers on this topic
Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network
VPS35-mediated APP recycling to the TGN is crucial for efficient A40 production, with A40 predominantly generated in the trans-Golgi network.
In Vitro Study
Highly CitedNot just amyloid: physiological functions of the amyloid precursor protein family
Amyloid precursor protein and its related proteins play crucial roles in CNS development, synapse formation, brain injury, neuroprotection, and ageing, with implications for therapeutic approaches.
Highly CitedThe Transcriptionally Active Amyloid Precursor Protein (APP) Intracellular Domain Is Preferentially Produced from the 695 Isoform of APP in a β-Secretase-dependent Pathway*♦
The APP intracellular domain (AICD) is preferentially synthesized from the APP695 isoform, which is associated with increased amyloid- levels and neprilysin expression in neuronal cells.
In Vitro StudyHighly CitedMolecular Characteristics of Amyloid Precursor Protein (APP) and Its Effects in Cancer
Amyloid precursor protein (APP) plays a crucial role in Alzheimer's disease and neuronal homeostasis, but also plays a role in various cancers.
Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα
APPs shows potential as a therapeutic target for Alzheimer's disease and other disorders, with potential benefits in neurotrophic, neuroprotective, neurogenic, and memory enhancement.
Highly CitedIdentification and differential expression of a novel alternative splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells.
A novel alternative splice site in leukocytes and brain microglial cells may lead to a potentially pathogenic processing of leukocyte-derived APP in the brain.
In Vitro StudyHighly CitedAPP-BP1, a Novel Protein That Binds to the Carboxyl-terminal Region of the Amyloid Precursor Protein (*)
APP-BP1 is a novel protein that binds to the -amyloid precursor protein, providing insights into the normal function of APPs and their potential role in Alzheimer's disease.
Highly CitedAmyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease.
Proteolytic processing of amyloid precursor protein may contribute to neurodegeneration in Alzheimer's disease, with single nucleotide polymorphisms in regulatory regions potentially contributing to age-related changes.
Highly CitedStudy of the synthesis and secretion of normal and artificial mutants of murine amyloid precursor protein (APP): cleavage of APP occurs in a late compartment of the default secretion pathway
APP-secretase is located in a late compartment of the default secretion pathway, with sorting signals in the cytoplasmic domain playing a crucial role in APP's deviation from the secretase pathway.
In Vitro StudyHighly CitedAmyloid Precursor Protein Trafficking, Processing, and Function*
Amyloid precursor protein (APP) plays a crucial role in Alzheimer's disease pathogenesis by regulating intracellular trafficking and amyloidogenic processing.
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