{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Amyloid precursor‐like protein 1 (APLP1) is a member of the APP family that displays several distinctive functional attributes. Unlike APP and APLP2, APLP1 is predominantly localized at the cell surface where it participates in trans‐cellular interactions and mediates cell adhesion (with its robust capacity for trans interaction)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Proteolytic processing studies have demonstrated that APLP1 is cleaved by secretases in a manner similar to APP; it undergoes β‐ and γ‐secretase cleavage to release intracellular fragments that can engage in nuclear signaling through interactions with adaptor proteins (although its transcriptional activation potential in combination with partners such as JIP‐1 is relatively weak compared with that of APP)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Importantly, APLP1 processing is uniquely influenced by N‐glycosylation and leads to the secretion of APLP1‐derived peptides—termed APL1β peptides—which are detectable in cerebrospinal fluid and appear to correlate with Alzheimer’s disease pathology, suggesting a potential role as surrogate biomarkers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its processing and adhesive properties, APLP1 appears to modulate neuronal morphology. Deletion studies indicate that the absence of APLP1 (along with other APP family members) promotes neurite elongation, implying that under normal conditions, APLP1 may function to constrain neurite outgrowth and thereby influence synaptic organization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Recent evidence also implicates APLP1 as a receptor for pathogenic protein aggregates. In the context of Parkinson’s disease, the extracellular E1 domain of APLP1 binds with high affinity to the C‐terminal region of misfolded, fibrillar α–synuclein. This binding, which is enhanced by pathogenic post‐translational modifications such as phosphorylation, may facilitate the endocytosis and propagation of α–synuclein pathology from cell to cell, thus contributing to disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifaceted role of APLP1 in neuronal function: from its regulated processing and involvement in nuclear signaling to its contribution to cell adhesion, modulation of neurite architecture, and functioning as a receptor for disease‐associated protein aggregates. Although overlapping in many respects with its APP family members, APLP1 exhibits unique biochemical and cellular properties that may have important implications for both neurodevelopment and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniela Kaden, Philipp Voigt, Lisa-Marie Munter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Subcellular localization and dimerization of APLP1 are strikingly different from APP and APLP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.034058"}], "href": "https://doi.org/10.1242/jcs.034058"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19126676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19126676"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Qiming Li, Thomas C Südhof "}, {"type": "b", "children": [{"type": "t", "text": "Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M310001200"}], "href": "https://doi.org/10.1074/jbc.M310001200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14699153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14699153"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Dominic M Walsh, Julia V Fadeeva, Matthew J LaVoie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi027375c"}], "href": "https://doi.org/10.1021/bi027375c"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12779321"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12779321"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Simone Eggert, Krzysztof Paliga, Peter Soba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The proteolytic processing of the amyloid precursor protein gene family members APLP-1 and APLP-2 involves alpha-, beta-, gamma-, and epsilon-like cleavages: modulation of APLP-1 processing by n-glycosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M311601200"}], "href": "https://doi.org/10.1074/jbc.M311601200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14970212"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14970212"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Kanta Yanagida, Masayasu Okochi, Shinji Tagami, et al. 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