An Infection Hypothesis to Explain the Amyloid Hypothesis of Alzheimer's Disease
Theory and evidence for persistent infection as a cause of Alzheimer's disease continues to grow in scope and plausibility. In general this supports rather than replaces past thinking on amyloid-β and its role in the development of Alzheimer's. It provides an explanation as to why it is that levels of amyloid-β rise over time to produce the early disruptions and changes in the biochemistry of the brain that are necessary for later neurodegeneration to take place. Other compelling lines of work provide evidence for entirely separate mechanisms by which levels of amyloid-β can grow in later life, such as declining drainage of cerebrospinal fluid. It seems plausible that all may be correct to some degree, and that many of these proposed processes are significant, each adding their own contribution to the progressive decline of the brain.
Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of phosphorylated tau (pTau). These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease.
Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients.
"An extensive microbiome comprised of bacteria, viruses, bacteriophages, and fungi is now understood to persist in nearly every human body site, including tissue and blood. The genomes of these microbes continually interact with the human genome in order to regulate host metabolism. Many components of this microbiome are capable of both commensal and pathogenic activity. They are additionally able to persist in both "acute" and chronic forms. Inflammatory conditions historically studied separately (autoimmune, neurological and malignant) are now repeatedly tied to a common trend: imbalance or dysbiosis of these microbial ecosystems. Population-based studies of the microbiome can shed light on this dysbiosis. However, it is the collective activity of the microbiome that drives inflammatory processes via complex microbe-microbe and host-microbe interactions. Many microbes survive as polymicrobial entities in order to evade the immune response. Pathogens in these communities alter their gene expression in ways that promote community-wide virulence. Other microbes persist inside the cells of the immune system, where they directly interfere with host transcription, translation, and DNA repair mechanisms. The numerous proteins and metabolites expressed by these pathogens further dysregulate human gene expression in a manner that promotes imbalance and immunosuppression. Molecular mimicry, or homology between host and microbial proteins, complicates the nature of this interference. When taken together, these microbe-microbe and host-microbe interactions are capable of driving the large-scale failure of human metabolism characteristic of many different inflammatory conditions."
http://www.discoverymedicine.com/Amy-D-Proal/2017/01/microbe-microbe-and-host-microbe-interactions-drive-microbiome-dysbiosis-and-inflammatory-processes/
Couldn't the lack of drainage also allow the infectious burden to grow?
How about microbial burden being a large part of ALL diseases of aging?
It certainly looks to be behind many cancers.