The Infection-Senescence Hypothesis of Alzheimer's Disease

With the continued failure of clinical trials of therapies for Alzheimer's disease, largely immunotherapies, that aim to clear amyloid-β, a growing faction of researchers are rejecting the amyloid hypothesis. In that mainstream view of the condition, the accumulation of amyloid-β causes the early stages of Alzheimer's, but in addition to disrupting the function of neurons, it also causes immune cells in the brain to become inflammatory, dysfunctional, and senescent. This in turn sets the stage for the aggregation of tau protein into neurofibrillary tangles, which causes widespread cell death and the much more severe manifestations of later stage Alzheimer's disease. Why do only some old people exhibit the condition? In the mainstream view, this is equivalent to asking why only some old people have significantly raised levels of amyloid-β in the brain. This might be due to different rates at which drainage of cerebrospinal fluid becomes impaired with aging, preventing molecular waste from leaving the brain. But many researchers are starting to consider that infectious pathogens are the most important cause, as amyloid-β has now been shown to be an antimicrobial peptide, a part of the innate immune system. The more infection, the more amyloid-β. There is good evidence for persistent infections such as forms of herpesvirus to be associated with Alzheimer's risk. In today's open access paper, the infection hypothesis is extended further to b...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs

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Genome-wide association study identifies CBFA2T3 affecting the rate of CSF Aβ42 decline in non-demented elders. Aging (Albany NY). 2019 Aug 01;11: Authors: Dou KX, Zhang C, Tan CC, Xu W, Li JQ, Cao XP, Tan L, Yu JT, Alzheimer’s Disease Neuroimaging Initiative (ADNI) Abstract Brain amyloid deposition is an early pathological event in Alzheimer's disease (AD), and abnormally low levels amyloid-β42 peptide (Aβ42) in cerebrospinal fluid (CSF) can be detected in preclinical AD. To identify the genetic determinants that regulate the rate of CSF Aβ42 decline among non-demented elder...
Source: Aging - Category: Biomedical Science Authors: Tags: Aging (Albany NY) Source Type: research
This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications. Gene Therapy in Mice Alters the Balance of Macrophage Phenotypes to Slow Atherosclerosis Progression https://www.fightaging.org/archives/2019/07/gene-therapy-in-mice-alters-the-balance-of-macrophage-phenotypes-to-slow-atherosclerosis-progression/ Atherosclerosis causes a sizable fraction of all deaths in our species. It is the generation of fatty deposits in blood vessel...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In conclusion, our study suggests that miR-200a-3p is implicated in the pathology of AD, exerting neuroprotective effects against Aβ-induced toxicity by two possible mechanisms: one involving the inhibition of Aβ overproduction via suppressing the expression of BACE1 and; two, synergistically, decreasing the hyperphosphorylation of tau via attenuating the expression of PKA.
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Anagliptin protects neuronal cells against endogenous amyloid β (Aβ)-induced cytotoxicity and apoptosis. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):2213-2220 Authors: Chen Z, Tao S, Li X, Zeng X, Zhang M, Yao Q Abstract Excessive generation and accumulation of amyloid-β (Aβ) fragments by familial mutations of amyloid precursor protein (APP) and presenilin 1 (PS1) play a key role in causing oxidative stress, mitochondrial abnormalities and neuronal apoptosis in Alzheimer's disease (AD). Anagliptin, a novel DPP-4 inhibitor, is a clinical drug for the management of type II diabetes...
Source: Artificial Cells, Nanomedicine and Biotechnology - Category: Biotechnology Tags: Artif Cells Nanomed Biotechnol Source Type: research
Necroptosis is a form of regulated necrosis that is implicated in various human diseases including Alzheimer’s disease. Necroptosis requires the translocation of the pseudokinase MLKL from the cytosol to the plasma membrane after its phosphorylation by the kinase RIPK3. Using protein cross-linking followed by affinity purification, we detected the lipid raft–associated proteins flotillin-1 and flotillin-2 and the ESCRT-associated proteins ALIX and syntenin-1 in membrane-localized MLKL immunoprecipitates. Phosphorylated MLKL was removed from membranes through either flotillin-mediated endocytosis followed by lys...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news
Abstract Necroptosis is a form of regulated necrosis that is implicated in various human diseases including Alzheimer's disease. Necroptosis requires the translocation of the pseudokinase MLKL from the cytosol to the plasma membrane after its phosphorylation by the kinase RIPK3. Using protein cross-linking followed by affinity purification, we detected the lipid raft-associated proteins flotillin-1 and flotillin-2 and the ESCRT-associated proteins ALIX and syntenin-1 in membrane-localized MLKL immunoprecipitates. Phosphorylated MLKL was removed from membranes through either flotillin-mediated endocytosis followed ...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research
In this study, C57BL/6 and Tau KO mice were used. For Tau KO mice, Western blot results of anti-Tau protein specific antibodies showed that Tau KO mice had no positive bands at 50–55 kDa (Tau protein position), while C57BL/6 mice normally expressed Tau protein (Figure 1).FIGURE 1Figure 1 Tau knockout (KO) mice did not express Tau protein.The C57BL/6 mice exhibited depressive behaviors, including anxiety, anhedonia, and depression-like after CUMS, and ketamine treatment alleviated their depressive behavior. Tau KO mice did not exhibit depressive behavior after CUMS. After treatment with ketamine at the same dose, ther...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
Abstract Mitochondria are crucial for neuronal cell survival and death through their functions in ATP production and the intrinsic pathway of apoptosis. Mitochondrial dysfunction is considered to play a central role in several serious human diseases, including neurodegenerative diseases, such as Parkinson's and Alzheimer's disease and ischemic neurodegeneration. The aim of the present study was to investigate the impact of transient global brain ischemia on the expression of selected proteins involved in mitochondrial dynamics and mitochondria‑associated membranes. The main foci of interest were the proteins mit...
Source: International Journal of Molecular Medicine - Category: Molecular Biology Authors: Tags: Int J Mol Med Source Type: research
Conclusion Taken together, evidence from animal and human studies demonstrates that the brain detects levels of circulating nutrients and hormones and consequently organizes an outward response that contributes to the regulation of whole-body glucose homeostasis. However, there are major knowledge gaps about the exact nature of this response and its relative importance compared to peripheral processes. As we have seen, animal studies have provided an anatomical map of CNS glucose regulation and have identified important neurons and neural circuits involved. Additionally, the CNS sensing of key nutrients and hormones has b...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
In conclusion, we unraveled the secretome of G. adiacens, an oral bacterium well-documented in infective endocarditis, but also recently shown to be involved in oral infections. Importantly, the secretome of G. adiacens comprised of a large number of putative virulence factors. Of particular importance is the finding that the G. adiacens secretome comprised of a number of “moonlighting” proteins, which in other species are shown to enhance bacterial colonization and virulence through their multifunctional roles (Pavkova et al., 2017; Graf et al., 2019). Thus, our results provide a basis for investigating the ro...
Source: Frontiers in cellular and infection microbiology - Category: Microbiology Source Type: research
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