Amyloid precursor protein (APP) is heavily implicated in the progression of Alzheimer’s disease. When proteolytically processed they yield 40 and 42 amino acid amyloid peptides which form the beta amyloid plaques one often hears about. APP/APLP2double knock-out mice have reduced protein expression at the neuromuscular synapse and have generally defective synapses. Wang et al have been studying this defect and have found that:
- APP synthesized in muscle and motor neurons end up in the pre and post synaptic sites at 1:1 stoichiometry, on the basis of antibody immunoreactivity.. This indicates that its expression at both sites is necessary for the proper development of the neuromuscular synapse.
- Postsynaptic APP deletion inhibits presynaptic vescicle release, indicating that the defects in synapse function are bidirectional.
- At embryonic day 12.5, APP expression is low, and nerve endings are not yet in contact with muscle. But at embryonic day 14.5 when synaptogenesis begins, APP expression spikes in both neural and muscle tissue. Major defects in the APP/APLP2 double knock out mutants don’t begin until embryonic day 16.5, perhaps because interaction between proteins across the synapse is necessary for proper function.
- After transfecting an APP expression construct into HEK293 cells with hippocampal neurons, the area of the cells covered by synaptophysin increased as compared to negative control, as did the number of synaptic puncta, both indicating that APP acts as a synaptic adhesion protein. Double knock out APP/APLP2 neurons had ~ 3 +/- 1 synaptic puncta per HEK293 cell as compared to ~ 10 +/- 1 for controls, further supporting the characterization of APP as necessary for synpatogenesis.
Downregulation of this synaptic adhesion property, which could possibly be inhibited by the beta amyloid plaques, would lead to the synaptic disfunction associated with Alzheimer’s pathogenesis. Perhaps a drug that inhibits the proteolytic enzyme that cleaves APP into amyloid peptides could act as a preventative drug for the disease for individuals with warning signs.
Wang et al. 2009 Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. Journal of Neuroscience 29:10788-10801. doi:10.1523/JNEUROSCI.2132-09.2009.