Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks

NEUROBIOLOGY OF AGING

卷:33

Article

Gleichmann, Marc¹  Zhang, Yongqing²  Wood, William H., III²  Becker, Kevin G.²  Mughal, Mohamed R.¹  Pazin, Michael J.³  van Praag, Henriette¹  Kobilo, Tali¹  Zonderman, Alan B.⁴  Troncoso, Juan C.⁵  Markesbery, William R.⁶  Mattson, Mark P.¹ 

[1] NIA, Neurosci Lab, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA

[2] NIA, Gene Express & Genom Unit, Res Resources Branch, Intramural Res Program,Biomed Res Ctr, Baltimore, MD 21224 USA

[3] NIA, Lab Cellular & Mol Biol, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA

[4] NIA, Res Resources Branch, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA

[6] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA

关键词: Alzheimer's disease;    Aging;    GABA;    Activity;    Homeostatic disinhibition;    Interneuron;    Calcium;    Synaptic scaling;   

DOI  :  10.1016/j.neurobiolaging.2010.08.012

来源: Elsevier

【 摘 要 】

Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer's disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca2+ signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca2+-mediated degeneration. Published by Elsevier Inc.

【 授权许可】

Free