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 bypass amyloid-β. The authors suggest that infection leads directly to the stage of chronic inflammation and senescent immune cells in the brain. Amyloid-β accumulation is not necessary for the progression of Alzheimer's in this view of the condition, and may be just a side-effect. As is usually the case in such matters, the best way to find out what is actually going on is to repair or block one mechanism in isolation of all of the others and see what happens. This is quite challenging in the case of Alzheimer's disease, as the animal models are all highly artificial: mice don't naturally suffer Alzheimer's or any similar condition. Thus one can reverse a mechanism or pathology that was introduced into the model, but that doesn't say much about what happens in the human condition, as it has quite different origins and progression.
Advanced age is a major Alzheimer's disease (AD) risk factor; therefore, understanding cellular senescence and its impact on endothelial cells (ECs), neurons, glia, and immune cells is an essential prerequisite for elucidating the pathogenesis of this condition. Brain accumulation of extracellular β-amyloid and intracellular hyperphosphorylated tau are the pathological hallmarks of AD. Both neurons and astrocytes synthesize β-amyloid from amyloid precursor protein (APP), while phagocytic microglia prevent its accumulation by removing it via the triggering receptor expressed on myeloid cells-2 (TREM-2).
The amyloid hypothesis postulates that accumulation and deposition of β-amyloid are the primary causes of AD, which promotes tau aggregation into neurofibrillary tangles (NFTs), ultimately triggering neuronal death. Although never universally accepted, the amyloid hypothesis drove AD research for at least two decades. Lately, however, many researchers and clinicians have questioned this model as amyloid removal failed to improve memory in numerous clinical trials. With the same token, neuroimaging studies detected significant β-amyloid deposits in 20-30% of healthy older individuals, while in many AD patients, this marker was not observed.
Moreover, β-amyloid was recently characterized as an antimicrobial peptide (AMP), and its accumulation in AD brains may be a reflection of increased microbial burden. AMPs are defensive biomolecules secreted by the innate immune system, including microglia and astrocytes, in response to a variety of microorganisms and malignant cells. The β-amyloid-AMP connection is further supported by the observation that central nervous system (CNS) infections were diagnosed in some clinical trials, following the administration of anti-amyloid vaccines.
Recent studies have reported co-localization of microorganisms with senescent neurons and glial cells in the brains of both AD patients and healthy older individuals, reviving the infectious hypothesis. CNS infectious agents have been detected previously in AD patients; however, it was difficult to assess if they represented the cause or effect of this condition. A recent study may have settled this issue as it detected gingipain, a Porphyromonas gingivalis antigen, linked to AD, in the brains of healthy older persons, suggesting that they would have developed the disease if they lived longer. As P. gingivalis is a major cause of gum disease and a modifiable AD risk factor, treatment of periodontal infection must be considered a clinical priority.
It has been well-established that inflammation and cellular senescence are closely related, but the role of pathogens in this process has been less emphasized. Astrocytes are the most numerous brain cells. Recent studies report that astrocytes are innate immune cells that, along with microglia, play a key role in the phagocytic removal of molecular waste, dead, or dying cells. Preclinical studies have reported that astrocytes undergo both replicative senescence and stress-induced senescence, however, the difference between senescent and reactive astrocytes is not entirely clear at this time. Recent studies seem to indicate that these phenotypes may be closely related or even identical as upregulated inflammatory and synapse-eliminating genes were found in both senescent and reactive astrocytes.
Dystrophic microglia with growth arrest and senescent markers have been demonstrated in AD patients, but the difference between the reactive and dystrophic phenotype is unclear at this time. Taken together, senescent microglia, incapable of proper immunosurveillance and phagocytosis, contribute to the accumulation of molecular waste, dead or dying cells, inducing inflammaging and immunosenescence. Astrocytes may respond to these microenvironmental changes by converting to a phenotype marked by aberrant elimination of healthy synapses and neurons, a possible pathogenetic mechanism of AD.
Thus, microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer's disease brains associated with senescent neurons, glia, and endothelial cells. We take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. Commensal gut microbes live in symbiosis with the human host as long as they reside in the GI tract where they can be kept under control. Cellular senescence alters the integrity of biological barriers, allowing translocation and dissemination of gut microorganisms throughout the body tissues, including the brain. Operating "behind enemy lines," pathogens can gain control of host immune defenses and metabolism, triggering senescence and neurodegenerative pathology.