Inflammatory changes parallel the early stages of Alzheimer disease
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
References (67)
- et al.
Genomic regulation after CD40 stimulation in microglia: relevance to Alzheimer's disease
Brain Res Mol Brain Res
(2005) - et al.
Inflammation and Alzheimer's disease
Neurobiol Aging
(2000) - et al.
Chemokines and their receptors in the central nervous system
Front Neuroendocrinol
(2001) - et al.
Genes, models and Alzheimer's disease
Trends Genet
(2001) - et al.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol–chloroform extraction
Anal Biochem
(1987) - et al.
Image analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity
Lancet
(1995) - et al.
Time course of the development of Alzheimer-like pathology in the doubly transgenic PS1 + APP mouse
Exp Neurol
(2002) - et al.
A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage
Biochem Biophys Res Commun
(1996) - et al.
Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer's disease brain tissue
Neurosci Lett
(1988) - et al.
Microglia-specific localisation of a novel calcium binding protein, Iba1
Brain Res Mol Brain Res
(1998)
HLA class I, II & III genes in confirmed late-onset Alzheimer's disease
Neurobiol Aging
Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease
Am J Pathol
The importance of inflammatory mechanisms in Alzheimer disease
Exp Gerontol
Frequency of HLA-A and B alleles in early and late-onset Alzheimer's disease
Neurosci Lett
Staging of cytoskeletal and beta-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer's disease
Am J Pathol
Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction
Neuron
Altered response to mirtazapine on gene expression profile of lymphocytes from Alzheimer's patients
Eur J Pharmacol
Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease
Neurobiol Aging
Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies
Neurobiol Aging
Intracellular pathways involved in TNF-alpha and superoxide anion release by Abeta(1–42)-stimulated primary human macrophages
J Neuroimmunol
Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases
J Neuroimmunol
Reactive microglia express class I and class II major histocompatibility complex antigens in Alzheimer's disease
Brain Res
Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial
JAMA
A Bayesian framework for the analysis of microarray expression data: regularized t -test and statistical inferences of gene changes
Bioinformatics
Brain-immune connection: immuno-regulatory properties of CNS-resident cells
Glia
Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses
Proc Natl Acad Sci USA
How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes
Aging Cell
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol (Berl)
Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling
J Neurosci Res
Focal inflammation in the brain: role in Alzheimer's disease
Immunol Res
Clinico-pathologic studies in dementia: nondemented subjects with pathologically confirmed Alzheimer's disease
Neurology
Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity
Ann Neurol
Microglia induce CD4 T lymphocyte final effector function and death
J Exp Med
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2022, Progress in NeurobiologyCitation Excerpt :They found that mismatch cases had significantly fewer CD68-positive microglia in addition to lower levels of hyperphosphorylated tau in synapses (Perez-Nievas et al., 2013). These data are in line with data from Parachikova and colleagues showing that mismatch cases in their dataset also have lower levels of MHC-II-positive microglia compared to AD cases with cognitive deficits (Parachikova et al., 2007), since both CD68 and MHC-II are traditionally considered markers of pro-inflammatory microglia activation. Histopathological studies that focused on microglial morphological characterization rather than expression of inflammatory markers yielded very different results (Sanchez-Mejias et al., 2016; Streit et al., 2009, 2014).