Are Microorganism's Responsible for Alzheimer's Disease?

Author's preface: As this is a review of a review article I do lean heavily on the original source material for much of the content. The original article is linked below. Be aware that if I do use words or phrasing from the original without attribution, that such attribution is implied. Feel free, and I highly encourage you, to read the original article and compare and contrast with my own summary of it.

Background

A fascinating paper (the author's refer to it as a "brief communication") published in the Journal Frontiers in Aging Neuroscience recently came to my attention. It provides a summary of some of the most compelling evidence linking pathogenic microbes to regressive neuropsychiatric diseases including autism, schizophrenia and Alzheimer's disease (AD). The review is speculative but the examples listed are specific and fairly convincing in my mind. Then again, as a microbiologist I am easy to convince when it comes to the importance of microorganisms for just about anything. My personal biases aside, the ten examples are illustrative and "provide insights into the potential contribution of pathogenic microbes, altered microbiome signaling and other disease-inducing agents to the development of AD." in the words of the paper's lead author James Hill of Louisina State University. For those who may not be aware Alzheimer’s disease is a progressive neurodegenerative disorder and surprisingly (or perhaps not) it is the leading cause of cognitive and behavioral impairment in industrialized societies. The cause or causes of AD remains unknown but we do know that age is the biggest risk factor. Only approximately 5% of all AD cases have an identifiable genetic or familial cause, with the vast majority of all AD cases (~95%) being of sporadic (unknown) origin.

Just as interesting as the main focus of the paper is the introduction and background section which provides a host of mind boggling and truly awe inspiring factoids about microorganisms and the human microbiome. The human microbiome consists of a complex and ever changing and evolving community of microorganisms that are associated with just about every major (non sterile) system of the human body. The numbers and diversity of microorganisms involved in the human microbiome are beyond massive and together they form a “metaorganism” with symbiotic or commensal benefit to the host, that would be you and me and every other member of of the human race. The largest reservoir of microorganisms making up our microbiome call the human gastrointestinal (GI) tract home. Estimates put that number at something like 10^14 microbes. For reference there are "only" 1 x 10^11 - 4 x 10^11 (100-400 billion) stars in the Milky Way galaxy so the number of microbes in your gut outnumber the stars in the galaxy by around 1000 fold. The densities of bacteria in our gut have been measured at up to 10^12 per ml, the highest recorded in any known microbial ecosystem. In the lab, using the most nutrient rich media and optimal growth conditions, we struggle to achieve bacterial densitives >10^8 per ml so the fact that it can happen in the gut tells you exactly how favorable it is for microbial growth. If all that doesn't blow your mind then you are not capable of having your mind blown. This unbelievably vast collection of microbes come from at least 1000 distinct species (99% bacteria with fungi, protozoa, archaebacteria, viruses, and other microorganisms making up the remainder). Together they outnumber our own human cells by about 100 to 1. Moreover, the genomes of the members of the GI tract have been estimated to encode about 4 × 10^6 genes so microbiome genes outnumber our own genes by about 150 to 1. Truly we are more microbe then man, and this is only the GI tract we are talking about. If we consider the microbiomes associated with the skin and other organ systems the numbers get even bigger and more mind boggling. If you are not familiar with large numbers and scientific notation for expressing them have a look at a piece I published a while back that has some information on the topic that may be helpful.

Here is where it gets really interesting however, the microbes that make up smallest 1% of the microbiome have a disproportionately large effect on disease. It has become increasingly clear, and this paper provides just a few examples specific to neurological disorders, that a major function of the healthy GI tract microbiome is to control the proliferation of any potentially pathogenic microbes that may also reside there. This process is referred to as homeostatic commensalism and when it breaks down pathogens can quickly increase in abundance. Increased numbers of pathogens in the gut has been associated with many diseases including anxiety, autoimmune-disease, diabetes, metabolic-syndrome, obesity, and stress-induced and progressive neuropsychiatric diseases including autism, schizophrenia and AD. Interest in the role of the microbiome in human health and disease has exploded in recent years. The advent and ascension of new sequencing (primarily what is referred to as next generation sequencing or NGS) and bioinformatics technologies have fueled the expansion. These techniques have allowed us to understand the genetics of complex microbial communities and microbial-host interactions.

Examples

I will highlight just three of the ten examples listed in the paper picking one that illustrates the role of pathogenic microbes from each of the major groups (bacteria, fungi, and viruses) relevant to AD in humans.

First up, fungi and infections of the central nervous system. Recently we have observed high levels of yeast and fungal proteins in the blood of AD patients. This suggests and least the possibility that chronic fungal infections may play a role in the development or progression of AD. Correlation is not causation, however AD is characterized in part by amyloid-containing senile plaques (SPs) and neurofibrillary tangles (NFTs) that induce microglial cell activation, neuroinflammation and brain and neurovascular cell dysfunction. And, interestingly, amyloids are associated with the surface structures of fungi.

Next up, pathogenic bacteria and AD. AD has been associated with the presence of Gram negative and other obligate intracellular bacteria of the family Chlamydiaceae. In addition to AD, these bacteria, which include pneumonia-causing C. pneumoniae, and C. trachomotis, causative agent of the sexually transmitted disease chlamydia in humans, are thought to play a role in diseases like coronary artery disease, arthritis, multiple sclerosis, and meningoencephalitis. Proteins (antigens) from C. pneumoniae have been found in the neocortex of brains of AD patients and associated with SP and NFT. Very interestingly, pneumonia is listed as the cause of death for almost all AD patients. Other studies have implicated Borrelia species, Helicobacter pylori (most known for its role in acid reflix disease), and bacteria associated with dieases of the teeth and gums such as the spirochaete Treponema denticola, and Porphyromonas gingivalis and others, with increased incidence of age-related dementias including AD.

Finally, viruses and AD. Both HIV-1 (human immunodeficiency virus, causitive agent of AIDS) and HSV-1 (herpes simplex virus, causative agent of herpes) have been associated with AD and other neurodegenerative disorders. Patients with HIV infections commonly manifest HIV-associated neurocognitive disorders (HAND). These disorders include a host of neurological conditions such as AIDS dementia complex, HIV-associated encephalopathy and AIDS-associated cognitive decline. When neural tissues are examined under the microscope with cell staining techniques HIV-infected brains show atrophy of neurites and neuronal loss in the areas identical to what is seen in AD. Misregulation of similar genes involved in neuroimmune response and synaptic transmission is also seen in both instances. There is a ton of evidence suggesting that HSV-1 can "live" in human CNS tissues for a persons entire life post infection and can contribute to AD. The papers author's say "A particularly interesting observation is that when human brain cells are infected with HSV-1, there is a significant and selective up-regulation in the expression of a small non-coding single-stranded RNA (ssRNA) known as miRNA-146a. This pro-inflammatory miRNA is also significantly up-regulated in anatomical areas of the human brain affected with AD. Out of ~2000 known miRNAs the same inducible, pro-inflammatory miRNA is specifically up-regulated in both AD and in HSV-1 infected brain cells....miRNAs regulate fundamental biological processes including immune recognition, promotion of cell survival, angiogenesis, cell proliferation and differentiation, but their contribution to the AD process is not well understood."