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Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain.

ABSTRACT: Degeneration of the cholinergic neurons in the basal forebrain and elevation of inflammatory markers are well-established hallmarks of Alzheimer's disease; however, the interplay of these processes in normal aging is not extensively studied. Consequently, we conducted a neuroanatomical investigation to quantify cholinergic neurons and activated microglia in the medial septum/vertical diagonal band (MS/VDB) of young (6 months) and aged (28 months) Fisher 344 × Brown Norway F(1) rats. Aged rats in this study were impaired relative to the young animals in spatial learning ability as assessed in the Morris water maze. Stereological analysis revealed no difference between aged and young rats in the total numbers of cholinergic neurons, demonstrating that loss of cholinergic neurons is not a necessary condition to observe impaired spatial learning in aged rats. In this same region, the total number of activated microglia was substantially greater in aged rats relative to young rats. Jointly, these data demonstrate that aging is characterized by an increase in the basal inflammatory state within the MS/VDB, but this inflammation is not associated with cholinergic neuron death.

SUBMITTER: McQuail JA

PROVIDER: S-EPMC2944908 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain.

McQuail Joseph A JA Riddle David R DR Nicolle Michelle M MM

Neurobiology of aging 20100618 12

Degeneration of the cholinergic neurons in the basal forebrain and elevation of inflammatory markers are well-established hallmarks of Alzheimer's disease; however, the interplay of these processes in normal aging is not extensively studied. Consequently, we conducted a neuroanatomical investigation to quantify cholinergic neurons and activated microglia in the medial septum/vertical diagonal band (MS/VDB) of young (6 months) and aged (28 months) Fisher 344 × Brown Norway F(1) rats. Aged rats in ...[more]

PMID: 20561717

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Project description:BackgroundNeuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer's disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD.MethodsSixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers.ResultsAdministration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS.ConclusionsColitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

Project description:BackgroundMedical advances have made it increasingly possible for spinal cord injury (SCI) survivors to survive decades after the insult. But how SCI affects aging changes and aging impacts the injury process have received limited attention. Extracellular vesicles (EVs) are recognized as critical mediators of neuroinflammation after CNS injury, including at a distance from the lesion site. We have previously shown that SCI in young male mice leads to robust changes in plasma EV count and microRNA (miR) content. Here, our goal was to investigate the impact of biological sex and aging on EVs and brain after SCI.MethodsYoung adult age-matched male and female C57BL/6 mice were subjected to SCI. At 19 months post-injury, total plasma EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis (NTA). EVs miR cargo was examined using the Fireplex® assay. The transcriptional changes in the brain were assessed by a NanoString nCounter Neuropathology panel and validated by Western blot (WB) and flow cytometry (FC). A battery of behavioral tests was performed for assessment of neurological function.ResultsTranscriptomic changes showed a high number of changes between sham and those with SCI. Sex-specific changes were found in transcription networks related to disease association, activated microglia, and vesicle trafficking. FC showed higher microglia and myeloid counts in the injured tissue of SCI/Female compared to their male counterparts, along with higher microglial production of ROS in both injured site and the brain. In the latter, increased levels of TNF and mitochondrial membrane potential were seen in microglia from SCI/Female. WB and NTA revealed that EV markers are elevated in the plasma of SCI/Male. Particle concentration in the cortex increased after injury, with SCI/Female showing higher counts than SCI/Male. EVs cargo analysis revealed changes in miR content related to injury and sex. Behavioral testing confirmed impairment of cognition and depression at chronic time points after SCI in both sexes, without significant differences between males and females.ConclusionsOur study is the first to show sexually dimorphic changes in brain after very long-term SCI and supports a potential sex-dependent EV-mediated mechanism that contributes to SCI-induced brain changes.

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Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain.

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Neuroinflammation not associated with cholinergic degeneration in aged-impaired brain.

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