Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease

Interactions of the presynaptic proteins, neuronal pentraxin 2 (NPTX2) and neurexin 2a (NRXN2a), with their respective postsynaptic functional partners, GluA4-containing glutamate (AMPA4) receptor and neuroligin 1 (NLGN1), enhance excitatory synaptic activity in some areas of the hippocampus and cerebral cortex. As early damage of such excitatory circuits in the brain tissues of participantswithAlzheimer's disease (AD) correlateswith cognitive losses, plasmaneuron-derived exosome (NDE) levels of these 2 pairs of specialized synaptic proteins were quantified to assess their biomarker characteristics. TheNDE contents of all 4 proteinswere decreased significantly inADdementia (n=46), anddiminished levels ofAMPA4andNLGN1 correlatedwiththe extent of cognitive loss. In a preclinical period, 6-11 yr before the onset of dementia, theNDE levels of all butNPTX2were significantly lower than those ofmatched controls, and levels of all proteins declined significantly with the development of dementia. Reductions inNDE levels of these specialized excitatory synaptic proteinsmay therefore be indicative of the extent of cognitive loss and may reflect progression of the severity of AD.-Goetzl, E. J., Abner, E. L., Jicha, G. A., Kapogiannis, D., Schwartz, J. B. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease. FASEB J. 32, 888-893 (2018). www.fasebj.org.