The Role of Synaptic Proteins in the Pathogenesis of Disorders of the Central Nervous System

Abstract

Complex sets of nervous system functions are dependent on proper working of the synaptic apparatus, and these functions are regulated by diverse synaptic proteins that are distributed in various subcellular compartments of the synapse. The most extensively studied synaptic proteins are synaptophysin, the synapsins, growth associated protein 43 (GAP-43), SV-2, and p65. Moreover, synaptic terminals contain a great number of other proteins involved in calcium transport, neurotransmission, signaling, growth and plasticity. Probes against various synaptic proteins have recently been used to study synaptic alterations in human disease, as well as in experimental models of neurological disorders. Such probes are useful markers of synaptic function and synaptic population density in the nervous system. For the present, we will review the role of synaptic proteins in the following conditions: Alzheimer's disease (AD) and other disorders including ischemia, disorders where synapse-associated proteins are abnormally accumulated in the nerve terminals, synaptic proteins altered after denervation, and synaptic proteins as markers in neoplastic disorders. The study of the molecular alterations of the synapses and of plasticity might yield important clues as to the mechanisms of neurodegeneration in AD, and of the patterns of presynaptic and dendritic damage under diverse pathological conditions.

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

“…This overall observation agrees with several earlier and recent contributions stressing the role of synapses in AD cognitive decline [8,18,28,42,43,58,59,68,71]. In particular, total numbers of spinophilin-immunoreactive puncta in the CA1 field and area 9 explain more than 20% and 60% of MMSE variability respectively.…”

“…Quantitative morphometric study of temporal and frontal cortical biopsies performed within an average of 2 to 4 years from the onset of clinical AD revealed 25 to 35% decrease in the numerical density of synapses and 15 to 35% decrease in the number of synapses per cortical neuron [15]. In terms of clinicopathologic correlations, much of the previous work has focused on loss of presynaptic markers such as synaptophysin [18,42,43,58,68,71]. The contribution of Terry and collaborators first implied that severity of AD is more robustly related to synapse loss than amyloid plaques, NFT densities, degree of neuronal loss, or extent of cortical gliosis [71].…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…Mounting evidence suggests that these are due to prominent synapse loss, particularly in the hippocampus and throughout the cortex [16][17][18][19][20], the principal areas affected in AD, and not to the loss of whole neurons. In fact, dendrite and synapse loss show a much stronger correlation with the associated cognitive decline than do neurofibrillary tangles or frank neuronal degeneration [17].…”

Defective Neuromuscular Synapses in Mice Lacking Amyloid Precursor Protein (APP) and APP-Like Protein 2

“…The pathology of AD is characterized by the deposition of ␤-amyloid plaques, of which the principal components are 40 and 42 amino acid ␤-amyloid peptides derived from the amyloid precursor protein (APP). Although ␤-amyloid plaques are the hallmark of AD, loss of synapses is closely associated with the duration and severity of cognitive impairment in AD patients (Terry et al, 1991;Masliah and Terry, 1993). These observations lead to the notion that synaptic dysfunction is a critical element of the pathogenesis of AD (Selkoe, 2002).…”