Abstract:Microbial infections of the brain can lead to dementia, and for many decades microbial infections have been implicated in Alzheimer's disease (AD) pathology. However, a causal role for infection in AD remains contentious, and the lack of standardized detection methodologies has led to inconsistent detection/identification of microbes in AD brains. There is a need for a consensus methodology; the Alzheimer's Pathobiome Initiative aims to perform comparative molecular analyses of microbes in post mortem brains v… Show more
“…The product of the key APOE gene, whose different alleles ( ɛ 2, ɛ 3, and ɛ 4, referred to as APOE2 – APOE4 ) modulate AD risk, binds tightly to Aβ [ 10 ] and APOE-derived peptides themselves have direct antimicrobial activity (e.g., [ 11–13 ] and references therein). Moreover, APOE modulates the risk of diverse infectious diseases (reviewed in [ 14 ]): APOE4 accelerates HIV proliferation whereas APOE3 is protective [ 15 ], there was a higher bacterial load in Chlamydia -infected homozygous APOE4 patients than in APOE2 / APOE3 carriers [ 16 ], and APOE4 increases susceptibility to herpes simplex lesions [ 17 ]. APOE4 is also a major determinant of severe COVID-19 (e.g., [ 18, 19 ]).…”
Section: Dementia and Infectionmentioning
confidence: 99%
“…Adding to the plausibility that infections might contribute to dementia, there have been a series of clinical cases in which dementia was found to be directly associated with fungal, bacterial, or viral infections, and in some cases dementia remitted following appropriate antimicrobial intervention (reviewed in [ 14 ]). Moreover, it has been argued that aging per se —the greatest risk factor for all types of dementia—is associated with decline of the immune system (immunosenescence) that predisposes to diverse infectious disorders including those of the central nervous system, as substantiated by increased levels of microbes in brain of elderly individuals [ 2 ].…”
There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer’s disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette–Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.
“…The product of the key APOE gene, whose different alleles ( ɛ 2, ɛ 3, and ɛ 4, referred to as APOE2 – APOE4 ) modulate AD risk, binds tightly to Aβ [ 10 ] and APOE-derived peptides themselves have direct antimicrobial activity (e.g., [ 11–13 ] and references therein). Moreover, APOE modulates the risk of diverse infectious diseases (reviewed in [ 14 ]): APOE4 accelerates HIV proliferation whereas APOE3 is protective [ 15 ], there was a higher bacterial load in Chlamydia -infected homozygous APOE4 patients than in APOE2 / APOE3 carriers [ 16 ], and APOE4 increases susceptibility to herpes simplex lesions [ 17 ]. APOE4 is also a major determinant of severe COVID-19 (e.g., [ 18, 19 ]).…”
Section: Dementia and Infectionmentioning
confidence: 99%
“…Adding to the plausibility that infections might contribute to dementia, there have been a series of clinical cases in which dementia was found to be directly associated with fungal, bacterial, or viral infections, and in some cases dementia remitted following appropriate antimicrobial intervention (reviewed in [ 14 ]). Moreover, it has been argued that aging per se —the greatest risk factor for all types of dementia—is associated with decline of the immune system (immunosenescence) that predisposes to diverse infectious disorders including those of the central nervous system, as substantiated by increased levels of microbes in brain of elderly individuals [ 2 ].…”
There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer’s disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette–Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.
“…During amyloidogenesis, Aβ forms toxic, soluble oligomers—implicated in neuronal death and disease pathology—prior to the deposition of mature fibrils 3 – 7 . Previously, Aβ aggregation was considered an inherently aberrant process, but recent studies suggest that aggregation may be triggered as a protective mechanism against microbial infection in the brain 8 – 18 . Figure 1 Amyloidogenesis of both Aβ and CsgA begins from a random coil, intrinsically disordered state and the formation of an aggregation-competent α-sheet monomer in the lag phase.…”
Section: Introductionmentioning
confidence: 99%
“…The neuroinflammatory response then reduces Aβ degradation and phagocytosis by microglia, further elevates microglial activation, and produces a cyclical loop of neurodegeneration 10 , 30 . The mechanism that triggers the initial upregulation of Aβ aggregation is still largely uncharacterized, but evidence of microbial pathogens in AD patient brain samples suggests that Aβ aggregation is employed as an innate immune response to microbial infection 8 , 10 , 12 , 16 – 18 , 26 . The microbial AD hypothesis postulates that although Aβ aggregation is likely a programmed immune response to microbial pathogens, the excess buildup of toxic Aβ aggregates results in a chronic inflammatory response that causes AD pathology 8 – 10 .…”
Section: Introductionmentioning
confidence: 99%
“…The mechanism that triggers the initial upregulation of Aβ aggregation is still largely uncharacterized, but evidence of microbial pathogens in AD patient brain samples suggests that Aβ aggregation is employed as an innate immune response to microbial infection 8 , 10 , 12 , 16 – 18 , 26 . The microbial AD hypothesis postulates that although Aβ aggregation is likely a programmed immune response to microbial pathogens, the excess buildup of toxic Aβ aggregates results in a chronic inflammatory response that causes AD pathology 8 – 10 . Notably, research suggesting that microbial infection triggers various types of dementia is well documented.…”
Colocalization of microbial pathogens and the β-amyloid peptide (Aβ) in the brain of Alzheimer’s disease (AD) patients suggests that microbial infection may play a role in sporadic AD. Aβ exhibits antimicrobial activity against numerous pathogens, supporting a potential role for Aβ in the innate immune response. While mammalian amyloid is associated with disease, many bacteria form amyloid fibrils to fortify the biofilm that protects the cells from the surrounding environment. In the microbial AD hypothesis, Aβ aggregates in response to infection to combat the pathogen. We hypothesize that this occurs through toxic Aβ oligomers that contain α-sheet structure and form prior to fibrillization. De novo designed α-sheet peptides specifically bind to the α-sheet structure present in the oligomers of both bacterial and mammalian amyloidogenic proteins to neutralize toxicity and inhibit aggregation. Here, we measure the effect of E. coli on Aβ, including upregulation, aggregation, and toxicity. Additionally, we determined the effect of Aβ structure on E. coli amyloid fibrils, or curli comprised of the CsgA protein, and biofilm formation. We found that curli formation by E. coli increased Aβ oligomer production, and Aβ oligomers inhibited curli biogenesis and reduced biofilm cell density. Further, curli and biofilm inhibition by Aβ oligomers increased E. coli susceptibility to gentamicin. Toxic oligomers of Aβ and CsgA interact via α-sheet interactions, neutralizing their toxicity. These results suggest that exposure to toxic oligomers formed by microbial pathogens triggers Aβ oligomer upregulation and aggregation to combat infection via selective interactions between α-sheet oligomers to neutralize toxicity of both species with subsequent inhibition of fibrillization.
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