Microglia and Aging in the Brain

Finch, Caleb E.; Morgan, Todd E.; Rozovsky, Irina; Xie, Zhong; Weindruch, Richard; Prolla, Tomas A.

doi:10.1007/978-1-4757-4139-1_13

Cited by 32 publications

(29 citation statements)

References 135 publications

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“…Analogous ECM͞adhesion pathways are also used by peripheral cells to suppress cancer cell invasion and metastasis during oncogenesis (66). Similarly, inflammatory responses, mediated by glial cells in the brain (17,18), also can be tumor-suppressive (67)(68)(69). Further, the generalized shutdown of protein metabolism seen here in early AD (Table 3) is a common manifestation of TS-mediated cellular senescence in some cell types (62).…”

Section: Discussionmentioning

confidence: 88%

“…Based primarily on MMSE criteria (35,46), subjects were categorized initially into four groups, termed ''Control'' (MMSE Ͼ25), ''Incipient AD'' (MMSE 20-26), ''Moderate AD'' (MMSE [14][15][16][17][18][19], and ''Severe AD'' (MMSE Ͻ14) ( Table 1). Several borderline cases (e.g., MMSE ϭ 26) were assigned based on NFT, amyloid plaque, and Braak stage data.…”

Section: Methodsmentioning

confidence: 99%

“…Multiple processes have been implicated in AD, notably including abnormal ␤-amyloid (A␤) production (1-7), tau hyperphosphorylation and neurofibrillary tangles (NFTs) (8,9), synaptic pathology (10)(11)(12), oxidative stress (13)(14)(15), inflammation (5,(16)(17)(18)(19), protein processing or misfolding (20,21), calcium dyshomeostasis (15,(20)(21)(22)(23)(24)(25)(26), aberrant reentry of neurons into the cell cycle (27,28), cholesterol synthesis (29,30), and effects of hormones (23,31) or growth factors (17,32). Nevertheless, the pathogenic factors that initiate these processes remain elusive.…”

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confidence: 99%

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Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Blalock

Geddes

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

944

853

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The pathogenesis of incipient Alzheimer's disease (AD) has been resistant to analysis because of the complexity of AD and the overlap of its early-stage markers with normal aging. Gene microarrays provide new tools for addressing complexity because they allow overviews of the simultaneous activity of multiple cellular pathways. However, microarray data interpretation is often hindered by low statistical power, high false positives or false negatives, and by uncertain relevance to functional endpoints. Here, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These well powered tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20). Biological process categories associated with incipient AD-correlated genes were identified statistically (EASE program) and revealed up-regulation of many transcription factor͞signaling genes regulating proliferation and differentiation, including tumor suppressors, oligodendrocyte growth factors, and protein kinase A modulators. In addition, up-regulation of adhesion, apoptosis, lipid metabolism, and initial inflammation processes occurred, and down-regulation of protein folding͞me-tabolism͞transport and some energy metabolism and signaling pathways took place. These findings suggest a new model of AD pathogenesis in which a genomically orchestrated up-regulation of tumor suppressor-mediated differentiation and involution processes induces the spread of pathology along myelinated axons. A lzheimer's disease (AD) has received intense study during past decades. Multiple processes have been implicated in AD, notably including abnormal ␤-amyloid (A␤) production (1-7), tau hyperphosphorylation and neurofibrillary tangles (NFTs) (8, 9), synaptic pathology (10-12), oxidative stress (13-15), inflammation (5, 16-19), protein processing or misfolding (20, 21), calcium dyshomeostasis (15,(20)(21)(22)(23)(24)(25)(26), aberrant reentry of neurons into the cell cycle (27, 28), cholesterol synthesis (29, 30), and effects of hormones (23, 31) or growth factors (17, 32). Nevertheless, the pathogenic factors that initiate these processes remain elusive.Several reasons account for the substantial resistance of AD pathogenesis to analysis. One is the vast extent and complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Another is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging, mild cognitive impairment, or incipient AD (33-35).We addressed the proble...

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Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Blalock

Geddes

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

944

853

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“…The antibody ED-1, which predominately labels activated macrophages and microglia (37)(38)(39), recognized few cells in untreated cultured slices (Fig. 1A).…”

Section: Statins Activate Microglia In Cultured Hippocampal Slices-mentioning

confidence: 99%

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Baudry

Liu

et al. 2004

Journal of Biological Chemistry

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Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration-and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-␣. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor-␣ but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease.High levels of cholesterol, and in particular of cholesterol esters (1), influence the generation and aggregation of ␤-amyloid peptides in dissociated cell cultures (2-6) and transgenic mice (7). Patients with high plasma cholesterol levels and cardiovascular diseases have increased risk of Alzheimer's disease (AD) 1 (8 -10), and there is evidence that statins, a family of compounds that inhibit the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase: HMG-CoA reductase), decrease the incidence of the disease (11, 12). These observations have led to an extensive and ongoing evaluation of statins as preventive treatments for Alzheimer's disease (13-16).Mevalonate, a cholesterol precursor, the synthesis of which is blocked by statins, is converted into several bioactive compounds. Among these, the isoprenoids are of particular importance because, among other functions, they provide for the covalent addition of lipid moieties (prenylation) to regulatory proteins (17) and thereby affect critical cell functions. Prenylation by the mevalonate products farnesyl diphosphate and geranylgeranyl diphosphate, ...

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“…Several biological processes have been associated with normal brain aging and neurodegenerative conditions, including inflammatory responses (Rogers et al, 1996;Murray and Lynch, 1998;Hauss-Wegrzyniak et al, 2000;Andreasson et al, 2001;Finch et al, 2002;Gemma et al, 2002;Wyss-Coray and Mucke, 2002), oxidative stress (Carney et al, 1991;Butterfield et al, 1999;Bickford et al, 2000;Nicolle et al, 2001;Wang et al, 2001), reduced mitochondrial function (Nicotera and Orrenius, 1998;Wallace, 2001), and altered Ca 2ϩ regulation (Landfield and Pitler, 1984;Michaelis et al, 1984;Gibson and Peterson, 1987;Khachaturian, 1989;Disterhoft et al, 1993;Franklin and Johnson, 1994;Lipton and Rosenberg, 1994;Foster and Norris, 1997;Nicotera and Orrenius, 1998;Verkhratsky and Toescu, 1998).…”

Section: Introductionmentioning

confidence: 99%

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

et al. 2003

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Gene expression microarrays provide a powerful new tool for studying complex processes such as brain aging. However, inferences from microarray data are often hindered by multiple comparisons, small sample sizes, and uncertain relationships to functional endpoints. Here we sought gene expression correlates of aging-dependent cognitive decline, using statistical profiling of gene microarrays in well powered groups of young, mid-aged, and aged rats (n ϭ 10 per group). Animals were trained on two memory tasks, and the hippocampal CA1 region of each was analyzed on an individual microarray (one chip per animal). Aging-and cognition-related genes were identified by testing each gene by ANOVA (for aging effects) and then by Pearson's test (correlating expression with memory). Genes identified by this algorithm were associated with several phenomena known to be aging-dependent, including inflammation, oxidative stress, altered protein processing, and decreased mitochondrial function, but also with multiple processes not previously linked to functional brain aging. These novel processes included downregulated early response signaling, biosynthesis and activity-regulated synaptogenesis, and upregulated myelin turnover, cholesterol synthesis, lipid and monoamine metabolism, iron utilization, structural reorganization, and intracellular Ca 2ϩ release pathways. Multiple transcriptional regulators and cytokines also were identified. Although most gene expression changes began by mid-life, cognition was not clearly impaired until late life. Collectively, these results suggest a new integrative model of brain aging in which genomic alterations in early adulthood initiate interacting cascades of decreased signaling and synaptic plasticity in neurons, extracellular changes, and increased myelin turnover-fueled inflammation in glia that cumulatively induce agingrelated cognitive impairment.

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Microglia and Aging in the Brain

Cited by 32 publications

References 135 publications

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia

Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment

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