Selective loss of synaptic proteins in Alzheimer's disease: evidence for an increased severity with APOE varepsilon4.
A pathological feature of Alzheimer's disease (AD) is an area-specific neuronal loss that may be caused by excitotoxicity-related synaptic dysfunction. Relative expression levels of synaptophysin, dynamin I, complexins I and II, N-cadherin, and alphaCaMKII were analysed in human brain tissue from AD cases and controls in hippocampus, and inferior temporal and occipital cortices. Synaptophysin and dynamin I are presynaptic terminal proteins not specific to any neurotransmitter system whereas complexin II, N-cadherin, and alphaCaMKII are specific for excitatory synapses. Complexin I is a presynaptic protein localised to inhibitory synapses. There were no significant differences in synaptophysin, dynamin I, N-cadherin, or alphaCaMKII protein levels between AD cases and controls. The complexin proteins were both markedly lower in AD cases than in controls (P < 0.01). Cases were also categorised by APOE genotype. Averaged across areas there was a 36% lowering of presynaptic proteins in AD cases carrying at least one epsilon4 allele compared with in AD cases lacking the epsilon4 allele. We infer that synaptic protein level is not indicative of neuronal loss, but the synaptic dysfunction may result from the marked relative loss of the complexins in AD, and lower levels of presynaptic proteins in AD cases with the APOE epsilon4 allele.
Tannenberg
Rudi K
RK
School of Molecular and Microbial Sciences, University of Queensland, Brisbane 4072, Queensland, Australia. r.tannenberg@uq.edu.au
Scott
Heather L
HL
Tannenberg
Anthony E G
AE
Dodd
Peter R
PR
D033942:Adaptor Proteins, Vesicular Transport; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053327:Apolipoprotein E4 / Q000235:genetics*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D015820:Cadherins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004252:DNA Mutational Analysis; D015536:Down-Regulation / Q000235:genetics; D034284:Dynamin I / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D053327:Apolipoprotein E4; D015820:Cadherins; D009419:Nerve Tissue Proteins; D016708:Synaptophysin; C095992:complexin I; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D034284:Dynamin I