Elsevier

Neurobiology of Aging

Volume 28, Issue 12, December 2007, Pages 1821-1833
Neurobiology of Aging

Inflammatory changes parallel the early stages of Alzheimer disease

https://doi.org/10.1016/j.neurobiolaging.2006.08.014Get rights and content

Abstract

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.

Introduction

AD is a chronic neurodegenerative disorder characterized by progressive memory deterioration. To elucidate the etiology of AD dementia, attempts have been made to correlate cognitive dysfunction with the classical neuropathological changes in AD, extracellular β-amyloid (Aβ) plaques, intraneuronal neurofibrillary tangles (NFTs), and synaptic/neuronal loss. However, some studies suggest that plaques and NFTs may not directly cause AD dementia since both pathologies can manifest in brains of patients that are not cognitively impaired [10], [14], [49], [56]. Another potential mechanism underlying dementia is synaptic loss, since synaptic markers are decreased in AD brains [16], [54], [59], [62]. However, evidence suggests that synaptic loss may occur only in moderate to severe clinical grades of dementia while early AD cases exhibit an increase in presynaptic markers [44]. Synaptic deficiency also correlates with the accumulation of soluble intraneuronal Aβ in AD vulnerable brain regions [34], [45]. Thus in accordance with the amyloid cascade hypothesis [19], [20], the accumulation of soluble Aβ with age may impair synaptic pathways associated with learning and memory.

Cognitive dysfunction in AD may also be critically influenced by Aβ-induced brain inflammation [3], [13], [37], [41], [61]. Specifically, Aβ accumulation leads to a site-specific activation of glia resulting in the secretion of pro-inflammatory cytokines [3], [13]. The inflammatory response may be an attempt to clear Aβ deposits; however, the progressive accumulation of Aβ and its aggregation into insoluble plaques may induce a chronic pro-inflammatory response leading to compromised neuronal function [8]. In support of a role for neuroinflammation in AD dementia, one study found a higher correlation between synapse loss and activated microglia than between Aβ deposits and NFTs [33]. Furthermore, some epidemiological studies demonstrate that non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or retard AD cognitive decline [29], [40], [52], [58], although other studies have found little improvement [1], [50]. This slowing of cognitive decline may be attributed to decreased inflammation since NSAID therapy substantially reduces the number of activated microglia associated with plaques [22], [36].

To better understand the factors contributing to AD dementia, this study aimed to identify critical changes in neuropathology and gene expression that occur during the transition into AD dementia, a very important and fundamental question in the field. Toward this goal, we compared the gene expression profiles followed by protein analyses in non-demented control patients and AD patients with mild to moderate clinical grades of dementia. Importantly, the majority of the cases comprising the control group were non-demented patients with high degree of AD-related pathology, thereby enabling us to identify factors that correlate with early cognitive decline in AD.

Section snippets

Case selection

The study employed stringent criteria for case selection based on Mini Mental State exam scores (MMSE), plaque and tangle density, sex, age, post-mortem interval (PMI), and RNA quality. Dementia severity was evaluated using the MMSE with scores of 25–30 indicating unimpaired cognition, 17–22 indicating mild/moderate dementia and less than 10 indicating severe dementia. BRAAK staging was employed to characterize pathology with stages I–II being normal to mild, stages III–IV being moderate and

Results

We aimed to identify gene expression and neuropathological changes in mild to moderate AD dementia cases (N = 10, MMSE 17–22, amyloid load 2.7–13.5%, BRAAK IV–V) compared to non-demented controls including 10 high plaque and/or tangle pathology controls (N = 14, MMSE 25–30, amyloid load 0–13.5%, BRAAK I–V) (Table 1). Importantly, the groups were chosen based on MMSE scores of cognitive functioning since plaque and tangle pathology does not always correlate with memory impairment.

The low MMSE group

Discussion

This study suggests that immune responses in the CNS may be involved in the transition to AD dementia. Our goal was to identify factors which correlate with cognitive decline by comparing non-demented controls, including high-pathology controls, to cases with mild/moderate clinical grades of AD dementia. We demonstrated that inflammatory molecules, most prominently MHC II, a marker of microglia activation, were increased in AD patients with early stage dementia. One prominent consequence of MHC

Acknowledgements

We would like to thank Dr. Kim Green and Dr. Danielle Simmons for the critical review of the manuscript. Also thanks to Dr. Kathryn Nichol for cell counting. The brain tissue was obtained from the Tissue Repository at the Institute for Brain Aging and Dementia and the Brain Donation Program at Sun Heath Research Institute. The Sun Health Research Institute Brain Donation Program is supported by the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center, the Arizona

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