Amyloid precursor protein (APP) and amyloid β-peptide (Aβ) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit α as a binding partner of the extracellular domain of APP and Aβ. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit α reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit α. The extracellular domain of APP and Aβ partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Aβ is similar in structure to the ATP synthase–binding sequence of the inhibitor of F1 (IF1), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Aβ and IF1 similarly impair both short- and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Aβ regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Aβ-mediated Alzheimer's disease pathology.

Carbohydrate-carrying molecules in the nervous system have important roles during development, regeneration and synaptic plasticity. Carbohydrates mediate interactions between recognition molecules, thereby contributing to the formation of a complex molecular meshwork at the cell surface and in the extracellular matrix. The tremendous structural diversity of glycan chains allows for immense combinatorial possibilities that might underlie the fine-tuning of cell–cell and cell–matrix interactions.

We have identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a binding partner for the cell adhesion molecule L1. GAPDH binds to sites within the extracellular domain of L1, namely the immunoglobulin-like domains I–VI and the fibronectin type III homologous repeats 4–5. Extracellular GAPDH was detected at the cell surface of neuronal cells by surface biotinylation and immunocytochemistry. Addition of GAPDH antibodies to cultured cerebellar neurons inhibited L1-dependent neurite outgrowth in the presence of ATP, while the application of exogenous GAPDH promoted L1-dependent neurite outgrowth. Pre-treatment of substrate-coated L1–Fc with ATP and GAPDH, which phosphorylates L1, subsequently led to an enhanced neurite outgrowth. Furthermore, aggregation of L1–Fc carrying beads was enhanced in the presence of both GAPDH and ATP. L1-dependent neurite outgrowth and aggregation of L1 were diminished in the presence of alkaline phosphatase or a protein kinase inhibitor. Our results show that GAPDH-dependent phosphorylation of L1 is a novel mechanism in regulating L1-mediated neurite outgrowth.