Cytokine Gene Expression as a Function of the Clinical Progression of Alzheimer Disease Dementia

Luterman, James D.; Haroutunian, Vahram; Yemul, Shrishailam; Ho, Lap; Purohit, Dushyant P.; Aisen, Paul S.; Mohs, Richard C.; Pasinetti, Giulio Maria

doi:10.1001/archneur.57.8.1153

Cited by 174 publications

(117 citation statements)

References 24 publications

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“…Previous studies have highlighted abnormal MHC II expression in AD [30,31,39,64] as well as in transgenic mouse models of AD [18,42,60], which suggests that these effects on MHC II are mediated by increased APP fragments including Aβ. In addition, severe late stage AD dementia has been correlated with increased MHC class II levels in the brain [4,35,67]. The current study provides evidence showing that the increase in MHC class II occurs earlier than previously described, is already present in cases with mild to moderate AD dementia and correlates inversely with MMSE scores.…”

Section: Discussionsupporting

confidence: 69%

Inflammatory changes parallel the early stages of Alzheimer disease

Parachikova

Agadjanyan

Cribbs

et al. 2007

Neurobiology of Aging

184

118

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Alzheimer disease (AD) is the most prominent cause of dementia in the elderly. To determine changes in the AD brain that may mediate the transition into dementia, the gene expression of approximately 10,000 full-length genes was compared in mild/moderate dementia cases to non-demented controls that exhibited high AD pathology. Including this latter group distinguishes this work from previous studies in that it allows analysis of early cognitive loss. Compared to non-demented high-pathology controls, the hippocampus of AD cases with mild/moderate dementia had increased gene expression of the inflammatory molecule major histocompatibility complex (MHC) II, as assessed with microarray analysis. MHC II protein levels were also increased and inversely correlated with cognitive ability. Interestingly, the mild/moderate AD dementia cases also exhibited decreased number of T cells in the hippocampus and the cortex compared to controls. In conclusion, transition into AD dementia correlates with increased MHC II + microglia-mediated immunity and is paradoxically paralleled by a decrease in T cell number, suggesting immune dysfunction.

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Section: Discussionsupporting

confidence: 69%

Inflammatory changes parallel the early stages of Alzheimer disease

Parachikova

Agadjanyan

Cribbs

et al. 2007

Neurobiology of Aging

184

118

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“…In particular, these syndromes have been associated with high levels of central and peripheral IL-1 and IL-6 (21)(22)(23)(24)(25)(26), with IL-6 levels predicting subsequent cognitive decline among the elderly (24,26,27). We have recently extended these findings to show an inverse association between IL-6 and memory function among relatively healthy mid-life adults, raising the possibility that IL-6 represents a novel biomarker for risk of future cognitive decline (28).…”

Section: Introductionmentioning

confidence: 79%

Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults

Marsland

Gianaros

Abramowitch

et al. 2008

Biological Psychiatry

309

224

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Background-Converging animal findings suggest that higher peripheral levels of inflammation are associated with activation of central inflammatory mechanisms that result in hippocampal neurodegeneration and related impairment of memory function. Consistent with animal findings, we have recently shown an inverse association between peripheral levels of interleukin-6 (IL-6), a relatively stable marker of systemic inflammation, and memory function in mid-life adults. In the current study, we extend this work to test whether systemic inflammation is associated with reduced grey matter volume of the hippocampus.

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“…The relevance of the A/T model for the study of altered brain hemodynamics in AD is strengthened not only by reports of TGF-␤1 up-regulation in the brain and vasculature of AD patients, [11][12][13][14]42 but also in elderly individuals who have suffered a stroke 43 and in subjects with hypertension and diabetes, 44 conditions that acutely or chronically limit cerebral blood flow and increase the risk for developing AD, 6,45 especially if they co-occur in the same individual. 46 In at-risk patients, TGF-␤1 could conceivably regulate A␤ production directly.…”

Section: Ad-like Cerebrovascular Pathology In A/t Mice and Therapeutimentioning

confidence: 99%

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

Ongali

Nicolakakis

Lecrux

et al. 2010

The American Journal of Pathology

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High brain levels of amyloid-␤ (A␤) and transforming growth factor-␤1 (TGF-␤1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in A␤ and TGF-␤1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular A␤ deposition, astrocyte activation , and impaired Morris water maze performance , which gained severity with age. The combined A␤-and TGF-␤1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring A␤ and TGF-␤1 increments.

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Cytokine Gene Expression as a Function of the Clinical Progression of Alzheimer Disease Dementia

Cited by 174 publications

References 24 publications

Inflammatory changes parallel the early stages of Alzheimer disease

Inflammatory changes parallel the early stages of Alzheimer disease

Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults

Transgenic Mice Overexpressing APP and Transforming Growth Factor-β1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease

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