Amyloid Precursor-Like Protein 2 (APLP2) is a protein found across various tissues, with a high presence in the brain. It is a type I transmembrane protein, meaning it spans the entire cell membrane, with a large domain extending outside the cell and a smaller tail inside the cell. APLP2 plays dual roles, supporting the healthy structure and communication of the nervous system while also becoming implicated in the progression of several diseases.
Defining APLP2 and Its Protein Family
APLP2 is one of three members of the Amyloid Precursor Protein (APP) family, alongside APP itself and Amyloid Precursor-Like Protein 1 (APLP1). These proteins share a highly conserved structural organization, which includes an extracellular domain, a transmembrane domain, and a short tail that resides within the cell cytoplasm. This shared structure allows for a degree of functional redundancy, especially within the nervous system.
While APP is widely known for its role as the precursor to the beta-amyloid peptide associated with Alzheimer’s disease, APLP2 does not contain the specific amino acid sequence that forms this pathological plaque. However, APLP2 is processed by the same set of enzymes, known as secretases, as APP. This shared processing machinery means that APLP2’s metabolism is intimately linked to the pathways that contribute to neurodegenerative conditions.
The importance of APLP2 is highlighted by genetic studies using mice where the genes for these proteins are inactivated. While removing a single family member often results in only minor abnormalities, the combined absence of APLP2 and either APP or APLP1 proves lethal shortly after birth. APLP2 and APP are broadly expressed throughout the body, whereas APLP1 expression is more restricted to neural tissues.
APLP2’s Role in a Healthy Nervous System
In a healthy nervous system, APLP2 is involved in communication and development between neurons. It functions as an adhesion molecule, helping cells stick together and regulate the physical connections that form synapses. The protein is present at both the presynaptic and postsynaptic sides of the synapse, supporting the formation and long-term maintenance of these junctions.
APLP2’s presence is important for synaptic function, where it helps regulate the transmission of signals between neurons. Studies have shown that when APLP2 is absent, particularly alongside APP, the excitatory synaptic transmission is deficient. Furthermore, APLP2 acts as a facilitator of neurotransmitter release, interacting directly with the machinery responsible for releasing chemical messengers into the synapse.
Beyond communication, APLP2 is also a player in neural development and plasticity. It promotes the outgrowth of neurites, which are projections from the neuron that develop into axons and dendrites. APLP2 also contributes to synaptic plasticity, which is the biological basis for learning and memory formation, including a mechanism called long-term potentiation (LTP). It has also been identified as a cargo receptor, helping to ferry intact proteins and other essential materials along the axon to their required destinations.
APLP2’s Contribution to Disease Pathology
APLP2’s structural similarity to APP means its processing is linked to mechanisms that drive neurodegenerative disorders. Like APP, APLP2 is cleaved by beta-secretase 1 (BACE1) and gamma-secretase enzymes, the same proteases that generate the toxic beta-amyloid peptide from APP. This processing generates fragments that can contribute to the overall pathology, even though APLP2 itself does not form the core beta-amyloid plaque. In the human brain, APLP2 fragments are predominantly cleaved by these secretases, indicating a strong metabolic connection to the Alzheimer’s pathway.
In addition to its neurological implications, APLP2 plays a role in the progression of various somatic cancers. The protein is frequently overexpressed in many tumor types, including pancreatic, breast, and colon cancers. In these contexts, APLP2 acts as a modulator of the cellular environment, promoting characteristics associated with aggressive disease.
APLP2 has been linked to increased tumor cell proliferation, which is the rapid growth and division of cancer cells. It also contributes to enhanced cell migration and invasion, processes necessary for the cancer to spread throughout the body and form metastases. The understanding of APLP2’s processing by secretases is now being explored as a potential target for future therapeutic strategies in both neurodegeneration and cancer.