Increased asynchronous release and aberrant calcium channel activation in amyloid precursor protein deficient neuromuscular synapses

Abstract

Despite the critical roles of the amyloid precursor protein (APP) in Alzheimer's disease pathogenesis, its physiological function remains poorly established. Our previous studies implicated a structural and functional activity of the APP family of proteins in the developing neuromuscular junction (NMJ). Here we performed comprehensive analyses of neurotransmission in mature neuromuscular synapse of APP deficient mice. We found that APP deletion led to reduced paired-pulse facilitation and increased depression of synaptic transmission with repetitive stimulation. Readily releasable pool size and total releasable vesicles were not affected, but probability of release was significantly increased. Strikingly, the amount of asynchronous release, a measure sensitive to presynaptic calcium concentration, was dramatically increased, and pharmacological studies revealed that it was attributed to aberrant activation of N-and L-type Ca 2+ channels. We propose that APP modulates synaptic transmission at the NMJ by ensuring proper Ca 2+ channel function.

Molecular Mechanisms for Synchronous, Asynchronous, and Spontaneous Neurotransmitter Release

“…Finally, in mouse models for degenerative disorders of the nervous system, such as spinal muscular atrophy (123) and Alzheimer’s disease (124), a shift from synchronous to asynchronous release during stimulation was observed. Asynchronous release from interneurons is also elevated in epileptiform tissue of rats and humans (125).…”

Role of APP and Aβ in Synaptic Physiology

“…Tissue specific deletion of APP/APLP2 in either presynaptic motoneuron or postsynaptic muscle results in abnormal NMJ synaptic transmission similar to the conventional APP/APLP2 dKO, implicating that both neuronal and muscle APP are necessary for normal NMJ synaptic activity [42]. APP deficient mouse demonstrates abnormal paired pulse response and enhanced asynchronous release at NMJ due to aberrant voltage gated calcium channel activity, including increased N-and L-type calcium channel (LTCC) activation at motor neuron terminals [86]. How the requirement of APP to cholinergic synaptic function relates to the toxic effects of A peptides remains to be determined.…”

Proteomic analysis of the presynaptic active zone

“…The structure of the entire APP E1 domain is reported by Dahms et al (2010). From top to the bottom: Heparin-binding domain (green), monoclonal antibody 22C11 binding site (teal), disulWde bridges (yellow), copper-binding domain (orange), zinc-binding domain (bright orange), acidic domain (Wrebrick), Kunitz protease inhibitor domain (blue), collagen-binding domain (violet), A sequence (cyan), secretase cleavage sites (pale cyan), transmembrane segment (dark teal), YENPTY sequence (magenta), NPXY sequence (purple), FE65 adaptor protein (white), not modeled rendered sequences (ruby) functional role of APP in concert with a variety of synaptic proteins in the central and peripheral nervous system (Soba et al 2005;Wang et al 2005Wang et al , 2007Yang et al 2007;Wang et al 2009). Mice deWcient in APP demonstrate aberrant activation of N-type and L-type calcium channels at the neuromuscular junction ).…”