The role of microbial infection in the pathogenesis of Alzheimer’s disease and the opportunity for protection by anti-microbial peptides

Li, Feijie; Hearn, Milton Thomas William; Bennett, Louise

doi:10.1080/1040841x.2021.1876630

Cited by 30 publications

(25 citation statements)

References 88 publications

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“…With age, both mitochondria and the microbiota deteriorate, and gut pathogens then have multiple options to either indirectly or directly wreak havoc on the brain (see section “Trouble in the Gut Is Trouble in the Brain”). Indeed, Alzheimer’s ( Fulop et al, 2018 ; Moir et al, 2018 ; Ashraf et al, 2019 ; Cryan et al, 2019 ; Li et al, 2021 ) and Parkinson’s ( Cardoso and Empadinhas, 2018 ; Nair et al, 2018 ; Cryan et al, 2019 ; Lubomski et al, 2019 ; Huang et al, 2021 ; Munoz-Pinto et al, 2021 ), along with many other mental afflictions ( Vuong et al, 2017 ; Cryan et al, 2019 ), tend to be both accompanied and preceded by not only mitochondrial dysfunction but also dysbiosis and intestinal disease (see also Vogt et al, 2017 ; Villumsen et al, 2019 ; Shen et al, 2021 ).…”

Section: The Roots Of Alzheimer’s and Parkinson’s Diseasementioning

confidence: 99%

“…Both beta-amyloid ( Moir et al, 2018 ) and alpha-synuclein ( Barbut et al, 2019 ) share several characteristics with substances like LL-37 that have well-established antimicrobial properties. In fact, they have anti-pathogenic properties themselves and they, or their soluble aggregates, boost immunity further by triggering inflammation ( D’Andrea, 2016 ; Park et al, 2016 ; Fulop et al, 2018 ; Li et al, 2018 ; beta-amyloid: Moir et al, 2018 ; Ashraf et al, 2019 ; alpha-synuclein: Barbut et al, 2019 ; Fitzgerald et al, 2019 ; Kowalski and Mulak, 2019 ; Li et al, 2021 ). In Alzheimer’s, beta-amyloid levels are typically rather high in the temporal lobes, which host the hippocampus ( Soscia et al, 2010 ).…”

Section: The Main Problem Is Pathogens Not Amyloidsmentioning

confidence: 99%

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Mitochondria-Microbiota Interaction in Neurodegeneration

Krämer

2021

Front. Aging Neurosci.

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Alzheimer’s and Parkinson’s are the two best-known neurodegenerative diseases. Each is associated with the excessive aggregation in the brain and elsewhere of its own characteristic amyloid proteins. Yet the two afflictions have much in common and often the same amyloids play a role in both. These amyloids need not be toxic and can help regulate bile secretion, synaptic plasticity, and immune defense. Moreover, when they do form toxic aggregates, amyloids typically harm not just patients but their pathogens too. A major port of entry for pathogens is the gut. Keeping the gut’s microbe community (microbiota) healthy and under control requires that our cells’ main energy producers (mitochondria) support the gut-blood barrier and immune system. As we age, these mitochondria eventually succumb to the corrosive byproducts they themselves release, our defenses break down, pathogens or their toxins break through, and the side effects of inflammation and amyloid aggregation become problematic. Although it gets most of the attention, local amyloid aggregation in the brain merely points to a bigger problem: the systemic breakdown of the entire human superorganism, exemplified by an interaction turning bad between mitochondria and microbiota.

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Section: The Roots Of Alzheimer’s and Parkinson’s Diseasementioning

confidence: 99%

Section: The Main Problem Is Pathogens Not Amyloidsmentioning

confidence: 99%

Mitochondria-Microbiota Interaction in Neurodegeneration

Krämer

2021

Front. Aging Neurosci.

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“…Again, no response was seen with any of the Aβ concentrations tested ranging from 1 to 10µM. Following the relatively new hypothesis that microbial presence in the brain could be a contributing factor to the development of AD in addition to Aβ accumulation [29][30][31][32] , we decided to test whether Aβ has any synergistic effect when the cells were co-primed with LPS and INFγ. We found no significant differences when treating THP-1 cells with this combination compared to LPS/INFγ alone.…”

Section: Synthetic Aβ Does Not Induce a Robust Transcriptional Responsementioning

confidence: 99%

Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems

Quiroga

Cruikshank²,

Reed³

et al. 2021

Preprint

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Alzheimer's disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aβ) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aβ is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e. microglia), which culminates in neuronal damage and cognitive decline. In order to test this hypothesis, many in vitro systems have been established to study Aβ-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale. To address this, we used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aβ. We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aβ does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aβ formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes similar to those observed in disease associated microglia present in the AD brain, suggesting the potential suitability of this model to study AD-related neuroinflammation.

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“…AD is a chronic neurodegenerative disorder characterized histopathologically by the presence of amyloid-β (Aβ) peptides in extracellular senile plaques and the formation of intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated, microtubule-associated protein tau. Because dementia can also arise from a number of etiologies that masquerade as or coexist with AD, pathological confirmation at autopsy (or rarely, biopsy in living individuals) has traditionally been necessary for definitive diagnosis [2] . In the last years, the World Health Organization (WHO) indicates dementia as a public health priority.…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of vitamin D supplements in the patients suffering from Alzheimer disease

Salat¹,

Mehta²

2021

Int. J. Adv. Res. Med.

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Introduction: Vitamin D is a steroid hormone. It crosses the blood brain barrier and binds with receptors present in neurons and glial cells of various parts of central nervous system like hippocampus, cortex, sub-cortex etc. Due to its antioxidant property and regulating intra-neuronal calcium homeostasis, it can be hypothesized that vitamin D has a role to play in preventing age related cognitive decline. Materials and Methods: Total of 160 patients were included in the study. MMSE is useful for evaluating the subjects having dementia syndrome because these subjects cooperate well only for short duration. Mini Mental state examination score was used for the assessment of dementia. They were included in the study on the basis of serum vitamin D level and MMSE score. Results: The collected data showed that mean serum vitamin D levels were found to be lower in group A when compared to group B. After 3 months of treatment with supplements, the score of post treatment MMSE was found to be higher in group A as compared to group B. After 6 months of treatment with supplements, the score of post treatment MMSE was found to be higher in group A as compared to group B. Discussion & Conclusion: Vitamin D acts like a neurosteroid hormone in areas of neurotransmission and neuro-immunomodulation. Patients on medical therapy for dementia has also shown improve results with regulation of vitamin D. It has also exhibited neuro-protective properties against glutamate toxicity through antioxidant effects thus preventing apoptosis. The present study is one of on-going steps in the direction of establishing role of Vitamin D in prevention and treatment of senile dementia.

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The role of microbial infection in the pathogenesis of Alzheimer’s disease and the opportunity for protection by anti-microbial peptides

Cited by 30 publications

References 88 publications

Mitochondria-Microbiota Interaction in Neurodegeneration

Mitochondria-Microbiota Interaction in Neurodegeneration

Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems

Effectiveness of vitamin D supplements in the patients suffering from Alzheimer disease

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