Occurrence of HLA‐DR Reactive Microglia in Alzheimer's Disease

McGeer, P. L.; Itagaki, S.; Tago, Hisao; McGeer, Edith G.

doi:10.1111/j.1749-6632.1988.tb27086.x

Cited by 53 publications

(34 citation statements)

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“…First, MHC class II expression was restricted to microglia cells and these cells colocalized with Aβ, suggesting that Aβ may be an antigen being presented. MHC class II expression in activated microglia associated with plaques has been previously established [53] [38,48]. Second, the presence of T cells in the hippocampus of mild to moderate AD dementia cases, as well as controls, suggests a potential for a T cell response.…”

Section: Discussionmentioning

confidence: 81%

Inflammatory changes parallel the early stages of Alzheimer disease

Parachikova

Agadjanyan

Cribbs

et al. 2007

Neurobiology of Aging

181

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: Discussionmentioning

confidence: 81%

Inflammatory changes parallel the early stages of Alzheimer disease

Parachikova

Agadjanyan

Cribbs

et al. 2007

Neurobiology of Aging

181

118

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“…Finally, besides being hyper reactive in AD, 85 microglia may also become dysfunctional or senescent as disease progresses, as indicated by the association of fragmented microglia with tau pathology. 86 This observation would also explain the attenuation of neuroinflammation in AD patients with increasing age, 87 and supports the role of inflammation early in the pathogenesis of AD.…”

Section: Aged and Primed Microgliamentioning

confidence: 99%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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“…Various degrees of microglia activation are seen in neurodegenerative disorders. Neuritic plaques, which constitute the central pathology in Alzheimer's disease (AD), are surrounded by microglia (McGeer et al, 1988b). In multiple sclerosis, areas of demyelination are rich in activated microglia (Bauer et al, 1994).…”

Section: Microglia In Neurodegenerationmentioning

confidence: 99%

The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: From pathology to imaging

Venneti

Lopresti

Wiley

2006

Progress in Neurobiology

339

330

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Microglia constitute the primary resident immune surveillance cell in the brain and are thought to play a significant role in the pathogenesis of several neurodegenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and HIV-associated dementia. Measuring microglial activation in vivo in patients suffering from these diseases may help chart progression of neuroinflammation as well as assess efficacy of therapies designed to modulate neuroinflammation. Recent studies suggest that activated microglia in the CNS may be detected in vivo using Positron Emission Tomography (PET) utilizing pharmacological ligands of the mitochondrial peripheral benzodiazepine receptor (PBR). Beginning with the molecular characterization of PBR and regulation in activated microglia, we examine the rationale behind using PBR ligands to image microglia with PET. Current evidence suggests these findings might be applied to the development of clinical assessments of microglial activation in neurological disorders.

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Occurrence of HLA‐DR Reactive Microglia in Alzheimer's Disease

Cited by 53 publications

References 1 publication

Inflammatory changes parallel the early stages of Alzheimer disease

Inflammatory changes parallel the early stages of Alzheimer disease

Deciphering the mechanism underlying late-onset Alzheimer disease

The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: From pathology to imaging

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