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Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression., (© 2011 Podtelezhnikov et al.)

During reproductive aging, female rodents show impaired inducibility of the estradiol (E2)-induced (preovulatory) surge of luteinizing hormone (LH), which is associated with hypothalamic neuronal impairments of aging. To evaluate if astrocytes show comparable age changes, we analyzed the regulation of glial fibrillary acidic protein (GFAP) mRNA which is transiently increased in the arcuate nucleus in association with the proestrus LH surge in young rats. In aging (18-month-old) F344 rats in persistent estrus, the loss of the E2-induced LH surge was paralleled by the lack of increased GFAP mRNA in the arcuate nucleus (in situ hybridization with X-ray film). We then tested the hypothesis that restoration of the LH surge by chronic ovariectomy (OVX) in aging rats would restore or block GFAP mRNA induction, respectively. Despite restoration of the inducible LH surge in aging rats by chronic OVX, there was no induction of GFAP mRNA in the arcuate nucleus. Moreover, young rats given chronic E2 implants for 6 weeks as a model for persistent estrus, retained induction of arcuate nucleus GFAP mRNA, despite loss of the induced LH surge. The aging rats were highly sensitive to gross pituitary enlargement from chronic E2 with 50% mortality; thus, the F344 genotype is not optimum for studies of aging-E2 interactions that require prolonged E2 treatments. More detailed cellular level analysis of GFAP mRNA is needed to define the relationship of GFAP expression to synaptic reorganization during the LH surge. The aging rats also showed higher levels of GFAP mRNA in the arcuate nucleus and ventromedial nucleus, consistent with the general trend for elevated GFAP mRNA during aging in other brain regions and in both sexes., (Copyright 2002 S. Karger AG, Basel)

Age and estrogen treatment influenced fiber outgrowth and compensatory neuronal sprouting after unilateral entorhinal cortex lesions (ECL) which model Alzheimer disease-like deafferentation in the dentate gyrus of the hippocampus. In young F344 rats (3 months old), ovariectomy (OVX) decreased reactive fiber outgrowth by 60%. Sprouting in middle-aged rats (18 months old) was reduced in intact females; no further reduction was caused by OVX. Several astrocyte mRNAs were measured in the dentate gyrus of young and middle-aged female rats in three different estrogen states (sham OVX, OVX, or OVX + estradiol) 1 week after ECL. Glial fibrillary acidic protein (GFAP) mRNA was twofold greater in middle-aged rats than young, although both ages showed threefold increases in response to ECL. In prior studies GFAP was found to be decreased by estradiol treatment 3-4 days after ECL; in this study GFAP mRNA had returned to sham OVX levels in young rats by 7 days post-ECL. Surprisingly, estradiol treatment increased GFAP mRNA levels by 25% above OVX in middle-aged rats. Apolipoprotein E (apoE) mRNA was decreased 20% by age in the dentate, although both age groups showed a 25% increase in apoE mRNA in response to ECL. Apolipoprotein J (apoJ) mRNA was increased 20% in the dentate gyrus of middle-aged rats, and both age groups responded to ECL with a 65% increase in apoJ mRNA. The estrogen state did not alter levels of either apolipoprotein mRNA in the deafferented dentate. The data suggest that the estrogen-induced decrease of GFAP in response to lesions does not persist at 7 days post-ECL during sprouting. Overall effects of age on the dentate gyrus include elevated GFAP mRNA and decreased apoE mRNA. The cortical wound site showed consistent enhancement of GFAP mRNA in both age groups by estradiol above sham OVX and greater responses in middle-aged rats., (Copyright 2000 Academic Press.)

Glial fibrillary acidic protein (GFAP), an intermediate filament of astrocytes, shows increased expression during aging. Because we found that chronic food restriction retards the increase of GFAP mRNA in aging rats and because food restriction decreases the load of oxidized proteins and lipids in association with increased life span, we investigated the regulation of GFAP during oxidative stress and aging. First, we showed that food restriction decreased the transcription of GFAP in aging rats. This result generalizes effects of food restriction on age changes of transcription; whether transcription decreases during aging as in hepatic genes, or increases during aging as in astrocytic GFAP, food restriction attenuates the age change. Moreover, food restriction decreased microglial activation during aging, which suggested the hypothesis that GFAP expression is sensitive to oxidative stress. Because GFAP transcription in cultured glia is increased by oxidative stress in response to hydrogen peroxide and cysteamine whether or not microglia were present, we conclude that responses of GFAP to oxidative stress in astrocytes do not depend on microglial activation. The results implicate oxidative stress in the increased expression of GFAP during aging, but also in responses to brain injury.

During aging, rodent and human brains show progressive increases in the levels of glial fibrillary acidic protein (GFAP) mRNA and protein. The role of transcription was investigated by in situ hybridization, using an intron-containing cRNA probe as a measure of primary GFAP transcripts. We found parallel age-related increases in GFAP intron RNA in the hippocampus, internal capsule, and corpus callosum of 3 versus 24 month old male F344 rats. We conclude that increased transcription supports the age-related increase of GFAP mRNA and protein. GFAP is a unique example of a gene that shows increased expression during aging in contrast to the decreased transcription of certain genes reported in non-neural tissues.