Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome.
Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane proteins supporting synaptic integrity and neurotransmission were downregulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an important role of DHA in synaptic function. In this study, we demonstrate aging-induced synaptic proteome changes and DHA-dependent mitigation of such changes using mass spectrometry-based protein quantitation combined with western blot or messenger RNA analysis. We found significant reduction of 15 synaptic plasma membrane proteins in aging brains including fodrin-α, synaptopodin, postsynaptic density protein 95, synaptic vesicle glycoprotein 2B, synaptosomal-associated protein 25, synaptosomal-associated protein-α, N-methyl-D-aspartate receptor subunit epsilon-2 precursor, AMPA2, AP2, VGluT1, munc18-1, dynamin-1, vesicle-associated membrane protein 2, rab3A, and EAAT1, most of which are involved in synaptic transmission. Notably, the first 9 proteins were further reduced when brain DHA was depleted by diet, indicating that DHA plays an important role in sustaining these synaptic proteins downregulated during aging. Reduction of 2 of these proteins was reversed by raising the brain DHA level by supplementing aged animals with an omega-3 fatty acid sufficient diet for 2 months. The recognition memory compromised in DHA-depleted animals was also improved. Our results suggest a potential role of DHA in alleviating aging-associated cognitive decline by offsetting the loss of neurotransmission-regulating synaptic proteins involved in synaptic function.
Laboratory of Molecular Signaling, DICBR, NIAAA, NIH, Bethesda, MD, USA.
Vishaldeep K
VK
Sidhu
Laboratory of Molecular Signaling, DICBR, NIAAA, NIH, Bethesda, MD, USA.
Bill X
BX
Huang
Laboratory of Molecular Signaling, DICBR, NIAAA, NIH, Bethesda, MD, USA.
Abhishek
A
Desai
Laboratory of Molecular Signaling, DICBR, NIAAA, NIH, Bethesda, MD, USA.
Karl
K
Kevala
Laboratory of Molecular Signaling, DICBR, NIAAA, NIH, Bethesda, MD, USA. Electronic address: hykim@nih.gov.
Hee-Yong
HY
Kim
D000375:Aging / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000209:etiology; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000502:physiology*; D015536:Down-Regulation; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D008568:Memory; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D020543:Proteome; D021641:Recognition, Psychology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics* / Q000502:physiology*
D015525:Fatty Acids, Omega-3; D008565:Membrane Proteins; D020543:Proteome; D004281:Docosahexaenoic Acids
Aging-related changes; DHA; MS–based protein quantitation; Mass spectrometry; Neurotransmission; Recognition memory; Synaptic plasma membrane proteins