Synaptic Genes Are Extensively Downregulated Across Multiple Brain Regions in Normal Human Aging and Alzheimer's Disease

Overview

Journal Neurobiol Aging

Publisher Elsevier

Specialties Geriatrics
Neurology
Physiology

Date 2013 Jan 1

PMID 23273601

Citations 154

Authors

Nicole C Berchtold

Paul D Coleman

David H Cribbs

Joseph Rogers

Daniel L Gillen

Carl W Cotman

Affiliations

Soon will be listed here.

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.

Citing Articles

Biomarker Identification for Alzheimer's Disease Using a Multi-Filter Gene Selection Approach.

Pashaei E, Pashaei E, Aydin N Int J Mol Sci. 2025; 26(5).

PMID: 40076442 PMC: 11898513. DOI: 10.3390/ijms26051816.

Identification of critical genes and drug repurposing targets in entorhinal cortex of Alzheimer's disease.

Hosseinpouri A, Sadegh K, Zarei-Behjani Z, Dehghan Z, Karbalaei R Neurogenetics. 2025; 26(1):27.

PMID: 39928227 DOI: 10.1007/s10048-025-00806-x.

Massive changes in gene expression and their cause(s) can be a unifying principle in the pathobiology of Alzheimer's disease.

Coleman P, Delvaux E, Kordower J, Boehringer A, Huseby C Alzheimers Dement. 2025; 21(2):e14555.

PMID: 39912452 PMC: 11851168. DOI: 10.1002/alz.14555.

Synaptic vulnerability to amyloid-β and tau pathologies differentially disrupts emotional and memory neural circuits.

Capilla-Lopez M, Deprada A, Andrade-Talavera Y, Martinez-Gallego I, Coatl-Cuaya H, Sotillo P Mol Psychiatry. 2025; .

PMID: 39885298 DOI: 10.1038/s41380-025-02901-9.

Forgetting is comparable between healthy young and old people.

Studer M, Heinemann D, Gutbrod K, Henke K Sci Rep. 2024; 14(1):31176.

PMID: 39732797 PMC: 11682405. DOI: 10.1038/s41598-024-82570-w.

References

Kang H, Kawasawa Y, Cheng F, Zhu Y, Xu X, Li M . Spatio-temporal transcriptome of the human brain. Nature. 2011; 478(7370):483-9. PMC: 3566780. DOI: 10.1038/nature10523. View

Kalisch T, Ragert P, Schwenkreis P, Dinse H, Tegenthoff M . Impaired tactile acuity in old age is accompanied by enlarged hand representations in somatosensory cortex. Cereb Cortex. 2008; 19(7):1530-8. DOI: 10.1093/cercor/bhn190. View

Epelbaum J, Guillou J, Gastambide F, Hoyer D, Duron E, Viollet C . Somatostatin, Alzheimer's disease and cognition: an old story coming of age?. Prog Neurobiol. 2009; 89(2):153-61. DOI: 10.1016/j.pneurobio.2009.07.002. View

Morrison J, Baxter M . The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci. 2012; 13(4):240-50. PMC: 3592200. DOI: 10.1038/nrn3200. View

Bannerman D . Fractionating spatial memory with glutamate receptor subunit-knockout mice. Biochem Soc Trans. 2009; 37(Pt 6):1323-7. DOI: 10.1042/BST0371323. View

Ginsberg S, Alldred M, Che S . Gene expression levels assessed by CA1 pyramidal neuron and regional hippocampal dissections in Alzheimer's disease. Neurobiol Dis. 2011; 45(1):99-107. PMC: 3220746. DOI: 10.1016/j.nbd.2011.07.013. View

Liang W, Dunckley T, Beach T, Grover A, Mastroeni D, Ramsey K . Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set. Physiol Genomics. 2008; 33(2):240-56. PMC: 2826117. DOI: 10.1152/physiolgenomics.00242.2007. View

Sperling R, Dickerson B, Pihlajamaki M, Vannini P, LaViolette P, Vitolo O . Functional alterations in memory networks in early Alzheimer's disease. Neuromolecular Med. 2010; 12(1):27-43. PMC: 3036844. DOI: 10.1007/s12017-009-8109-7. View

Ibi D, Nitta A, Ishige K, Cen X, Ohtakara T, Nabeshima T . Piccolo knockdown-induced impairments of spatial learning and long-term potentiation in the hippocampal CA1 region. Neurochem Int. 2009; 56(1):77-83. DOI: 10.1016/j.neuint.2009.09.004. View

10.

de Leon M, George A, Golomb J, Tarshish C, Convit A, Kluger A . Frequency of hippocampal formation atrophy in normal aging and Alzheimer's disease. Neurobiol Aging. 1997; 18(1):1-11. DOI: 10.1016/s0197-4580(96)00213-8. View

11.

Hara Y, Park C, Janssen W, Punsoni M, Rapp P, Morrison J . Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J Neurosci. 2011; 31(21):7737-44. PMC: 3103072. DOI: 10.1523/JNEUROSCI.0822-11.2011. View

12.

Masdeu J, Kreisl W, Berman K . The neurobiology of Alzheimer disease defined by neuroimaging. Curr Opin Neurol. 2012; 25(4):410-20. DOI: 10.1097/WCO.0b013e3283557b36. View

13.

Ehrlich I, Malinow R . Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. J Neurosci. 2004; 24(4):916-27. PMC: 6729816. DOI: 10.1523/JNEUROSCI.4733-03.2004. View

14.

Corradi A, Zanardi A, Giacomini C, Onofri F, Valtorta F, Zoli M . Synapsin-I- and synapsin-II-null mice display an increased age-dependent cognitive impairment. J Cell Sci. 2008; 121(Pt 18):3042-51. DOI: 10.1242/jcs.035063. View

15.

Tan M, Chua W, Esiri M, Smith A, Vinters H, Lai M . Genome wide profiling of altered gene expression in the neocortex of Alzheimer's disease. J Neurosci Res. 2009; 88(6):1157-69. DOI: 10.1002/jnr.22290. View

16.

Jahn R, Scheller R . SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol. 2006; 7(9):631-43. DOI: 10.1038/nrm2002. View

17.

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

18.

Peters A, Sethares C, Luebke J . Synapses are lost during aging in the primate prefrontal cortex. Neuroscience. 2008; 152(4):970-81. PMC: 2441531. DOI: 10.1016/j.neuroscience.2007.07.014. View

19.

Vanguilder H, Yan H, Farley J, Sonntag W, Freeman W . Aging alters the expression of neurotransmission-regulating proteins in the hippocampal synaptoproteome. J Neurochem. 2010; 113(6):1577-88. PMC: 3010414. DOI: 10.1111/j.1471-4159.2010.06719.x. View

20.

Nicholson D, Yoshida R, Berry R, Gallagher M, Geinisman Y . Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments. J Neurosci. 2004; 24(35):7648-53. PMC: 6729620. DOI: 10.1523/JNEUROSCI.1725-04.2004. View