Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease

Abstract

Synapses are essential for transmitting, processing, and storing information, all of which decline in aging and Alzheimer's disease (AD). Because synapse loss only partially accounts for the cognitive declines seen in aging and AD, we hypothesized that existing synapses might undergo molecular changes that reduce their functional capacity. Microarrays were used to evaluate expression profiles of 340 synaptic genes in aging (20-99 years) and AD across 4 brain regions from 81 cases. The analysis revealed an unexpectedly large number of significant expression changes in synapse-related genes in aging, with many undergoing progressive downregulation across aging and AD. Functional classification of the genes showing altered expression revealed that multiple aspects of synaptic function are affected, notably synaptic vesicle trafficking and release, neurotransmitter receptors and receptor trafficking, postsynaptic density scaffolding, cell adhesion regulating synaptic stability, and neuromodulatory systems. The widespread declines in synaptic gene expression in normal aging suggests that function of existing synapses might be impaired, and that a common set of synaptic genes are vulnerable to change in aging and AD.

Fig. 1

Aging and Alzheimer’s disease (AD) undergo unique region-specific patterns of synaptic gene responses, with the vast majority of genes downregulated. (A) In normal aging, neocortical regions (superior frontal gyrus [SFG], postcentral gyrus [PCG]) undergo extensive synaptic gene expression change, and limbic regions (hippocampus [HC], entorhinal cortex [EC]) show relatively little significant transcriptional change (p < 0.01, young vs. aged). (B) In AD, only the HC showed extensive synaptic gene expression changes, and relatively little transcriptional change was detected in the EC and SFG. Essentially no gene expression change was detected in the PCG (p < 0.01, aged vs. AD).

Fig. 2

Numerous synaptic genes appear to undergo a progressive transcriptional change that is initiated in aging and continues in Alzheimer’s disease (AD). (A) Genes showing a progressive change across Aging-AD were most prevalent in the superior frontal gyrus (SFG) and hippocampus (HC), with relatively less change occurring in the entorhinal cortex (EC) and postcentral gyrus (PCG). (B) Signature profiles of Aging-AD genes in the SFG. (C) Signature profiles of Aging-AD genes in the HC. Abbreviations: A, aged; Y, young.

Fig. 3

Quantitative polymerase chain reaction (qPCR) was undertaken in hippocampal tissue to validate the age- and Alzheimer’s disease (AD)-related changes derived from the gene chip studies for VAMP2 (synaptobrevin 2), SNAP25 (synaptosomal-associated protein-25), synaptophysin, GRIN1 (glutamate NMDA receptor 1), muscarinic cholinergic receptor 3 (CHARM3), serotonin receptor 2a (5HTR2a), and somatostatin (SST) using hippocampal tissue from 29 samples (young control, n = 9; aged control, n = 10; AD, n = 10). (A) qPCR data confirmed widespread downregulation of these synaptic genes in aging, with further downregulation in AD. Comparison of relative expression changes derived from qPCR and microarray analysis (B) for the same set of samples revealed a high correspondence between the 2 methods.