Neuroinflammatory responses in Alzheimer’s disease

Dansokho, Cira; Heneka, Michael T.

doi:10.1007/s00702-017-1831-7

Cited by 110 publications

(74 citation statements)

References 111 publications

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“…Midlife obesity is a risk factor of LOAD, but the biological mechanisms underpinning this link remain poorly understood. Both conditions are associated with systemic inflammation, and it is increasingly recognised that microglia-mediated immune responses play an important role in LOAD (Dansokho and Heneka, 2018;Heneka et al, 2015;Sarlus and Heneka, 2017;Tejera and Heneka, 2016). It has therefore been proposed that obesity induced gut dysbiosis may trigger micro-glia mediated neuroinflammation that in turn may contribute to the development of LOAD pathology (Bartzokis, 2011;Sochocka et al, 2018;Venegas et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix

Metzler‐Baddeley

Mole

Leonavičiūtė

et al. 2018

Preprint

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Midlife obesity is a risk factor of late onset Alzheimer’s disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, one possibility is that obesity-related neuroinflammation may contribute to the development of LOAD. Neuroinflammation is closely linked to white matter myelin loss, and this can be measured in vivo with quantitative magnetization transfer (qMT) imaging. Here, we investigated whether differences in obesity measures, i.e., in Waist Hip Ratio (WHR), abdominal visceral and subcutaneous fat volume fractions and Body Mass Index (BMI), were associated with reductions in qMT indices of apparent myelin in temporal white matter pathways involved in LOAD (i.e., the fornix, the parahippocampal cingulum and the uncinate fasciculus compared with whole brain and cortico-spinal white matter) in 166 cognitively healthy individuals (38-71 years of age). Obesity-related effects on myelin-sensitive markers were contrasted with differences in apparent axon density from dual-shell diffusion Neurite Orientation Dispersion and Density Imaging (NODDI). Differences in WHR and in visceral fat volume fractions were negatively correlated with differences in qMT estimates of apparent myelin and tissue metabolism in the fornix but not with any other microstructural components. These correlations were not explained by demographic (age, sex, education), health (hypertension, alcohol consumption, sedentary lifestyle) or genetic (APOE genotype, family history of dementia) risk factors of LOAD. Furthermore, differences in the ratio of plasma concentrations of leptin and adiponectin were also positively correlated with differences in C-Reactive Protein concentrations, and contributed significantly to the correlations between central obesity and myelin-sensitive metrics in the fornix. These results are consistent with the view that visceral fat-related chronic inflammation may damage white matter myelin in limbic regions, known to be vulnerable to LOAD pathology.

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Section: Discussionmentioning

confidence: 99%

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix

Metzler‐Baddeley

Mole

Leonavičiūtė

et al. 2018

Preprint

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“…Such changes in the offspring's brain may lead to brain dysfunction in the long term. Neuroinflammation has been found in various brain conditions, especially during the development of neurodegenerative disease . Brain aging can also be accelerated by cigarette smoking, which may be replicated in smoker's offspring.…”

Section: Potential Cellular Mechanismsmentioning

confidence: 99%

“…Brain aging can also be accelerated by cigarette smoking, which may be replicated in smoker's offspring. The formation of β‐amyloid, the hallmark of the development of Alzheimer's disease, can be increased if brain levels of TLR4, IL‐1, and IL‐6 are high . Additionally, increased levels of IL‐6 in the brain has also been linked to increased anxiety‐like behaviour .…”

Section: Potential Cellular Mechanismsmentioning

confidence: 99%

“…Neuroinflammation has been found in various brain conditions, especially during the development of neurodegenerative disease. 62,63 Brain aging can also be accelerated by cigarette smoking, 64 which may be replicated in smoker's offspring. The formation of β-amyloid, the hallmark of the development of Alzheimer's disease, can be increased if brain levels of TLR4, IL-1, and IL-6 are high.…”

Section: Inflammatory Responses In the Brainmentioning

confidence: 99%

“…The formation of β-amyloid, the hallmark of the development of Alzheimer's disease, can be increased if brain levels of TLR4, IL-1, and IL-6 are high. 63 Additionally, increased levels of IL-6 in the brain has also been linked to increased anxiety-like behaviour. 65 In the animal model, male offspring from the SE dams displayed an early decline in short-term memory and significantly higher levels of anxiety even before puberty.…”

Section: Inflammatory Responses In the Brainmentioning

confidence: 99%

See 2 more Smart Citations

What lessons have we learnt about the impact of maternal cigarette smoking from animal models?

Chan

Oliver

Chen

2019

Clin Exp Pharma Physio

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Maternal first‐ or second‐hand tobacco smoking during pregnancy is still common albeit that the detrimental effects to the unborn child are well known. Maternal tobacco cigarette smoking can affect multiple organ systems in the offspring, rendering them at increased risk of various conditions throughout life (eg. intrauterine underdevelopment, asthma, substance abuse, diabetes). However, this review will only focus on its impact on the brain and the related molecular changes in the offspring based on evidence from animal studies. Although epidemiological studies have identified the associations between maternal cigarette smoke exposure (SE) and brain disorders, animal models can help identify the underlying mechanisms and test interventions. Human studies have found that maternal SE is closely linked to small brain size and changes in brain structure and associated with a high risk of cognitive defects. Animal models suggest that this may be due to increased brain oxidative stress and inflammation during the neonatal period, leading to increased brain cell apoptosis in adulthood. There is a distinct gender bias of such impacts, where male offspring are more affected than females. Female offspring seem to have developed the adaptation by increasing endogenous antioxidant levels. Indeed, animal studies have shown that using antioxidant supplementation during pregnancy can improve neurological outcomes in male offspring, however, the efficacy in humans is yet to be confirmed. Furthermore, some animal studies suggested nicotine as the key player in intrauterine underdevelopment due to maternal SE, while human clinical trials using nicotine replacement therapy do not support this mechanism. This review will discuss the possible reasons.

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Amyloid‐β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease

Sanchez-Mico

Jiménez

Gómez-Arboledas

et al. 2020

Glia

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Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid‐β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid‐β peptides), Tau (containing AT8‐ and AT100‐positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs‐APP, but not AT8/AT100‐positive SNs‐Tau, as compared with SNs‐WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12‐month‐old APP mice, since only 1.60 ± 3.81% of peri‐plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia‐mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia‐dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid‐β alone. Taken together, our data suggest that amyloid‐β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid‐β, as well as of peri‐plaque dystrophic synapses containing amyloid‐β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.

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Neuroinflammatory responses in Alzheimer’s disease

Cited by 110 publications

References 111 publications

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix

What lessons have we learnt about the impact of maternal cigarette smoking from animal models?

Amyloid‐β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease

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