Fight Aging!

There are a lot of papers on Alzheimer's disease that fall outside the mainstream focus on the formation of amyloid in the brain. This is perhaps in part a consequence of the challenges and delays that have beset efforts to produce practical treatments based on the amyloid view of the progression of Alzheimer's. As soon as any consensus in medical research and development fails to keep up its momentum, there are factions nibbling at its heels and trying out other ideas. The past few decades of the broader field of medical science are littered with promising approaches discarded in favor of others in the course of a few short years. Some of the alternative views of Alzheimer's disease are far out on the fringes, while others explore plausible contributions to the disease process wherein any debate must start with "yes, but is this a meaningful effect in comparison to others?" or "perhaps, but this is happening a long way in to the chain of consequences and dysfunction."

Here is an outline of an interesting view on the contribution of microbial populations to the progression of Alzheimer's disease, both the symbiotic gut microbiota that are considered to influence aging to some degree, and the impact of a lifetime of exposure to hostile pathogens. These may turn out to be proxies for the state of the immune system or metabolic dysfunction due to obesity and old age, both of which are important in the progression of degenerative aging. It makes for interesting reading, but it is worth asking questions such as those above when looking at this sort of thing.

Pathogenic microbes, the microbiome, and Alzheimer's disease (AD)

Here we list 10 recent, highly specific and illustrative insights into the potential contribution of pathogenic microbes, altered microbiome signaling and other disease-inducing agents to the development of AD:

1) Fungal infection of the central nervous system (CNS): Recently yeast and fungal proteins including (1,3)-β-glucan, high levels of fungal polysaccharides and disseminated and diffuse mycoses in the peripheral blood of AD patients suggests that chronic fungal infections may increase AD risk.

2) HSV-1 is associated with AD: Abundant evidence suggests that the herpes simplex virus-1 (HSV-1), can establish lifelong latency in CNS tissues and contribute to AD.

3) Prion diseases: driven by an unusual type of self-replicating "microbe," prion diseases are sporadic, inherited or acquired and ultimately fatal neurological disorders highly similar to AD. The recent discovery that prions can serve as Aβ receptors to relay amyloid neurotoxicity, and that peripherally administrated prions reach the brain, has engendered renewed interest in this self-replicating protein and its involvement in AD-like signaling processes that include neuroinflammation, synaptic degeneration and amyloidogenesis.

4) Chlamydophila pneumoniae, other pathogenic bacteria and AD: The association of the gram negative, obligate intracellular bacteria and pneumonia-causing C. pneumoniae of the family Chlamydiaceae with diseases such as coronary artery disease, arthritis, multiple sclerosis, meningoencephalitis, and AD has recently gained serious attention.

5) HIV-1 and AD: HIV-associated neurocognitive disorders (HAND) is a common manifestation of HIV infection and encompasses a variety of neurological disorders. Histopathologically HIV-infected brains exhibit atrophy of neurites and neuronal loss in anatomical areas identical to what is seen in AD.

6) Toxoplasma and neurodegeneration: Toxoplasma species such as Toxoplasma gondii are intracellular protozoan parasites that can cause encephalitis and neurological dysfunction by promoting chronic inflammation of the brain and CNS. Recently AD has been associated with significantly increased anti-T. gondii antibodies suggesting a possible mechanistic link between T. gondii infection and AD.

7) Viroids, miRNAs and AD: viroids are minimalist plant pathogens that consist of a viroid-specific ssRNA that are remarkably similar to miRNAs in their mode of generation, processing, structure and function, mobility and ability to spread disease within the host. We may be able to gain insight on the mechanism of AD neuropathology driven by miRNA from what is already known about plant viroids and their ability to spread systemic degenerative disease.

8) Hepatitis and AD: Hepatitis C virus infection has recently been shown to significantly increase the risk for AD, especially in the aged.

9) Cytomegalovirus and AD: A growing number of common viruses and latent viral infections involving Herpesviridae have been linked to the development of AD, and one of these is the human cytomegalovirus (HCMV).

10) GI tract and blood-brain barrier permeability: Lastly and importantly, the GI tract epithelial barrier and the blood brain barrier both become significantly more permeable over the course of aging. This may make the CNS more susceptible to potential neurotoxins generated by microbiome-resident or environmental pathogens.

Taken together, it is clear that the human CNS is under constant assault by a wide array of extrinsic and intrinsic neurotrophic microbes and pathogens including bacteria, virus, fungus, nucleic-acid free prions, or small non-coding RNAs found both in the environment and contained within the microbiome. Virtually every type of microbe known has been implicated in contributing to the susceptibility and pathogenesis of the AD process. This may be especially important over the course of aging because innate-immune and physiological barriers are often compromised with age, enabling microbes and/or their 'neurotoxic secretions' to gain easier access to CNS compartments. Because AD is clearly a multifactorial disease, and there are multiple biological pathways by which brain cells can dysfunction, perhaps it is not too surprising that multiple and complex microbial insults could contribute to AD, including the spreading of pathological signals throughout the CNS.