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Homeostatic disinhibition in the aging brain and Alzheimer's disease.

ABSTRACT: In this article, we propose that impaired efficiency of glutamatergic synaptic transmission and a compensatory reduction in inhibitory neurotransmission, a process called homeostatic disinhibition, occurs in the aging brain and more dramatically in Alzheimer's disease (AD). Homeostatic disinhibition may help understand certain features of the aging brain and AD, including: 1) the increased risk for epileptic seizures, especially in the early phase of the disease; 2) the reduced ability to generate ?-oscillations; and 3) the increase in neuronal activity as measured by functional MRI. Homeostatic disinhibition may be the major mechanism that activates cognitive reserve. Modulating neuronal activity may therefore be a viable therapeutic strategy in AD that can complement existing anti-amyloid strategies. Specifically, enhancing endogenous glutamatergic synaptic transmission through increased co-agonist signaling or through positive allosteric modulation of metabotropic glutamatergic receptors appears as an attractive strategy. Alternatively, further reduction of GABAergic signaling may work as well, although care has to be taken to prevent epileptic seizures.

SUBMITTER: Gleichmann M

PROVIDER: S-EPMC4543386 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Homeostatic disinhibition in the aging brain and Alzheimer's disease.

Gleichmann Marc M Chow Vivian W VW Mattson Mark P MP

Journal of Alzheimer's disease : JAD 20110101 1

In this article, we propose that impaired efficiency of glutamatergic synaptic transmission and a compensatory reduction in inhibitory neurotransmission, a process called homeostatic disinhibition, occurs in the aging brain and more dramatically in Alzheimer's disease (AD). Homeostatic disinhibition may help understand certain features of the aging brain and AD, including: 1) the increased risk for epileptic seizures, especially in the early phase of the disease; 2) the reduced ability to genera ...[more]

PMID: 21187584

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Project description:Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer's disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and CD36 was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as CD68 (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [11C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.

Dataset Information

Homeostatic disinhibition in the aging brain and Alzheimer's disease.

Publications

Homeostatic disinhibition in the aging brain and Alzheimer's disease.

Similar Datasets

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