The viral hypothesis: how herpesviruses may contribute to Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Wainberg M
PROVIDER: S-EPMC8758477 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
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Project description:The so-called amyloid hypothesis, that the accumulation and deposition of oligomeric or fibrillar amyloid ? (A?) peptide is the primary cause of Alzheimer's disease (AD), has been the mainstream concept underlying AD research for over 20 years. However, all attempts to develop A?-targeting drugs to treat AD have ended in failure. Here, we review recent findings indicating that the main factor underlying the development and progression of AD is tau, not A?, and we describe the deficiencies of the amyloid hypothesis that have supported the emergence of this idea.
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Project description:Alzheimer's disease (AD) is the most common form of dementia in the elderly. Hallmark AD neuropathology includes extracellular amyloid plaques composed largely of the amyloid-? protein (A?), intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated microtubule-associated protein tau (MAP-tau), and microtubule destabilization. Early-onset autosomal dominant AD genes are associated with excessive A? accumulation, however cognitive impairment best correlates with NFTs and disrupted microtubules. The mechanisms linking A? and NFT pathologies in AD are unknown. Here, we propose that sequestration of zinc by A?-amyloid deposits (A? oligomers and plaques) not only drives A? aggregation, but also disrupts zinc homeostasis in zinc-enriched brain regions important for memory and vulnerable to AD pathology, resulting in intra-neuronal zinc levels, which are either too low, or excessively high. To evaluate this hypothesis, we 1) used molecular modeling of zinc binding to the microtubule component protein tubulin, identifying specific, high-affinity zinc binding sites that influence side-to-side tubulin interaction, the sensitive link in microtubule polymerization and stability. We also 2) performed kinetic modeling showing zinc distribution in extra-neuronal A? deposits can reduce intra-neuronal zinc binding to microtubules, destabilizing microtubules. Finally, we 3) used metallomic imaging mass spectrometry (MIMS) to show anatomically-localized and age-dependent zinc dyshomeostasis in specific brain regions of Tg2576 transgenic, mice, a model for AD. We found excess zinc in brain regions associated with memory processing and NFT pathology. Overall, we present a theoretical framework and support for a new theory of AD linking extra-neuronal A? amyloid to intra-neuronal NFTs and cognitive dysfunction. The connection, we propose, is based on ?-amyloid-induced alterations in zinc ion concentration inside neurons affecting stability of polymerized microtubules, their binding to MAP-tau, and molecular dynamics involved in cognition. Further, our theory supports novel AD therapeutic strategies targeting intra-neuronal zinc homeostasis and microtubule dynamics to prevent neurodegeneration and cognitive decline.
| S-EPMC3311647 | biostudies-literature
Project description:Converging evidence indicates that processes occurring in and around neuronal dendrites are central to the pathogenesis of Alzheimer's disease. These data support the concept of a "dendritic hypothesis" of AD, closely related to the existing synaptic hypothesis. Here we detail dendritic neuropathology in the disease and examine how A?, tau, and AD genetic risk factors affect dendritic structure and function. Finally, we consider potential mechanisms by which these key drivers could affect dendritic integrity and disease progression. These dendritic mechanisms serve as a framework for therapeutic target identification and for efforts to develop disease-modifying therapeutics for Alzheimer's disease.
| S-EPMC3989444 | biostudies-literature
Project description:A well-recognized theory of Alzheimer's disease (AD) pathogenesis suggests ectopic cell cycle events to mediate neurodegeneration. Vulnerable neurons of the AD brain exhibit biomarkers of cell cycle progression and DNA replication suggesting a reentry into the cell cycle. Chromosome reduplication without proper cell cycle completion and mitotic division probably causes neuronal cell dysfunction and death. However, this theory seems to require some inputs in accordance with the generally recognized amyloid cascade theory as well as to explain causes and consequences of genomic instability (aneuploidy) in the AD brain. We propose that unscheduled and incomplete DNA replication (replication stress) destabilizes (epi)genomic landscape in the brain and leads to DNA replication "catastrophe" causing cell death during the S phase (replicative cell death). DNA replication stress can be a key element of the pathogenetic cascade explaining the interplay between ectopic cell cycle events and genetic instabilities in the AD brain. Abnormal cell cycle reentry and somatic genome variations can be used for updating the cell cycle theory introducing replication stress as a missing link between cell genetics and neurobiology of AD.
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Project description:Gene drives are genetic modifications designed to propagate in a population with high efficiency. Current gene drive strategies rely on sexual reproduction and are thought to be restricted to sexual organisms. Here, we report on a gene drive system that allows the spread of an engineered trait in populations of DNA viruses and, in particular, herpesviruses. We describe the successful transmission of a gene drive sequence between distinct strains of human cytomegalovirus (human herpesvirus 5) and show that gene drive viruses can efficiently target and replace wildtype populations in cell culture experiments. Moreover, by targeting sequences necessary for viral replication, our results indicate that a viral gene drive can be used as a strategy to suppress a viral infection. Taken together, this work offers a proof of principle for the design of a gene drive in viruses.
| S-EPMC7522973 | biostudies-literature
Project description:DUX4 is a germline transcription factor and a master regulator of zygotic genome activation. During early embryogenesis, DUX4 is crucial for maternal to zygotic transition at the 8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In adult somatic cells, DUX4 expression is silenced and its activation in adult muscle cells causes the genetic disorder Facioscapulohumeral Muscular Dystrophy (FSHD). Here we show that herpesviruses actively induce DUX4 expression to promote viral transcription and replication. We demonstrate that HSV-1 immediate early proteins directly induce expression of DUX4 and its target genes including endogenous retroelements, which mimics zygotic genome activation. DUX4 directly binds to the viral genome, promotes viral transcription and genetic depletion of DUX4 by CRISPR/Cas9 abrogates viral replication. Our results show that viruses from alpha-, beta- and gamma-herpesvirus subfamilies induce DUX4 expression and downstream germline-specific genes and retroelements. Herpesviruses activate DUX4 expression in order to induce an early embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.
2023-06-11 | GSE234489 | GEO
Project description:Alzheimer's disease (AD) is characterised by the aggregation of two quite different proteins, namely, amyloid-beta (A?), which forms extracellular plaques, and tau, the main component of cytoplasmic neurofibrillary tangles. The amyloid hypothesis proposes that A? plaques precede tangle formation but there is still much controversy concerning the order of events and the linkage between A? and tau alterations is still unknown. Mathematical modelling has become an essential tool for generating and evaluating hypotheses involving complex systems. We have therefore used this approach to discover the most probable pathway linking A? and tau. The model supports a complex pathway linking A? and tau via GSK3?, p53, and oxidative stress. Importantly, the pathway contains a cycle with multiple points of entry. It is this property of the pathway which enables the model to be consistent with both the amyloid hypothesis for familial AD and a more complex pathway for sporadic forms.
| S-EPMC3296276 | biostudies-literature
Project description:The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (A?) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We elaborate on and update arguments for and against the amyloid hypothesis with new data and interpretations, and consider why the amyloid hypothesis may be failing therapeutically. We note several unresolved issues in the field including the presence of A? deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of A? oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the poorly explained pathological heterogeneity and comorbidities associated with AD. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease, can be interpreted independently of a role for A? in AD. We conclude it is essential to expand our view of pathogenesis beyond A? and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.
| S-EPMC4207354 | biostudies-other
Project description:Since 1992, the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer's disease (AD). It proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. While there is substantial evidence supporting the hypothesis, there are also limitations: (1) SP and NFT may develop independently, and (2) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD. In addition, randomized clinical trials that tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive. This paper provides a critical overview of the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions.
| S-EPMC3313573 | biostudies-literature