<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">APLP2 Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>APLP2</td></tr>
<tr><td><strong>Full Name</strong></td><td>Amyloid Beta Precursor-Like Protein 2</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>15q24.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[334](https://www.ncbi.nlm.nih.gov/gene/334)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[104776](https://www.omim.org/entry/104776)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000145087</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q06481](https://www.uniprot.org/uniprot/Q06481)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Down Syndrome](/diseases/down-syndrome), [Cognitive Decline](/diseases/cognitive-decline)</td></tr>
</table>
</div>
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">APLP2 Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>APLP2</td></tr>
<tr><td><strong>Full Name</strong></td><td>Amyloid Beta Precursor-Like Protein 2</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>15q24.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[334](https://www.ncbi.nlm.nih.gov/gene/334)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[104776](https://www.omim.org/entry/104776)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000145087</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q06481](https://www.uniprot.org/uniprot/Q06481)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Down Syndrome](/diseases/down-syndrome), [Cognitive Decline](/diseases/cognitive-decline)</td></tr>
</table>
</div>
The APLP2 gene encodes Amyloid Beta Precursor-Like Protein 2, the second and most widely expressed member of the APP family, which also includes APP and APLP1. Unlike APP, APLP2 cannot generate Abeta peptides due to sequence differences, but it plays essential and non-redundant roles in neuronal development, synaptic function, and behavior. APLP2 is unique among APP family members in that it is essential for viability, with knockout mice dying perinatally.
The APLP2 gene is located on chromosome 15q24.2 and encodes a protein of approximately 763 amino acids. The gene structure is highly conserved with other APP family members. APLP2 produces multiple splice variants with distinct expression patterns and functions, including full-length transmembrane isoforms, secreted isoforms, and brain-specific isoforms.
The APLP2 protein shares structural similarity with APP, containing an N-terminal signal peptide, large extracellular domain (E1 and E2 regions), transmembrane domain, and cytoplasmic tail (AICD) with conserved signaling motifs including the YENPTY motif for endocytic sorting. The KPI domain (Kunitz protease inhibitor) is present in some isoforms.
APLP2 has the broadest expression of all APP family members with highest levels in brain, heart, and skeletal muscle, and significant expression in lung, kidney, and liver. In the central nervous system, APLP2 is expressed in neurons, astrocytes, oligodendrocytes, and microglia, with regional distribution in cerebral cortex, hippocampus, cerebellum, thalamus, and hypothalamus.
APLP2 plays critical roles in synapse formation and function by promoting formation of excitatory synapses, regulating synaptic protein clustering, modulating postsynaptic density organization, regulating NMDA receptor function and trafficking, and influencing GABAergic signaling. It is required for long-term potentiation and depression and essential for learning and memory formation.
APLP2 provides neuroprotection through trophic support via secreted domains, activation of pro-survival signaling pathways, protection against excitotoxicity, and regulation of calcium homeostasis. It also functions as an adhesion molecule promoting cell-cell adhesion, guiding axonal growth and guidance, and regulating neuronal migration.
APLP2 functionally cooperates with APP and APLP1 through compensatory functions, direct interactions forming heterodimers, shared signaling pathways, and synergistic effects when combined.
While APLP2 cannot produce Aβ, it contributes to AD through amyloid-independent pathways including synaptic dysfunction through impaired NMDA receptor signaling, reduced LTP and LTD, and synaptic protein mislocalization. It also influences APP processing by competing for secretase access and modulating gamma-secretase activity.
APLP2 is critically involved in Down syndrome pathology. Although APP is on chromosome 21, APLP2 contributes to DS phenotypes through gene triplication effects that affect protein expression, contributing to early-onset neurodegeneration and synergy with APP/Aβ pathology.
While APLP2 cannot produce Aβ directly, targeting APLP2 may provide therapeutic benefits in AD:
APLP2-based therapeutic strategies under investigation include:
Key approaches for studying APLP2 include:
The following diagram shows the key molecular relationships involving APLP2 Gene discovered through SciDEX knowledge graph analysis: