Developmental regulation of amyloid precursor protein at the neuromuscularjunction in mouse skeletal muscle

Amyloid precursor protein (APP), associated with Alzheimer's disease plaque s, is known to be present in synapses of the brain and in the adult neuromu scular junction (NMJ). In the present study we examined protein and gene ex pression of APP during the development of mouse skeletal muscle. Using immu nocytochemical approaches, we found that APP is first detected in myotube c ytoplasm at embryonic day 16 and becomes progressively concentrated at the NMJ beginning at birth until adulthood. The colocalization between APP and acetylcholine receptors at the NMJ is only partial at birth, but becomes co mplete upon reaching adulthood. We observed that all APP isoforms, includin g the Kunitz-containing (protease inhibitor or KPI) forms, are up-regulated from birth to postnatal day 5 and then decreased to reach the low levels o bserved in the adult. This suggests the involvement of APP during the event s which lead to a mature mono-innervated synapse. A 92-kDa band, characteri stic of a cleaved APP695 isoform and not due to a new muscle-specific alter native spliced form, was observed from postnatal day 15 following completio n of polyneuronal synapse elimination. Taken together, these data suggest t hat skeletal muscle APP may well play a role in the differentiation of skel etal muscle and in the formation and maturation of NMJs.