Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer’s Disease

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

CHOLINERGIC SYSTEM RESPONSE TO STRESS AND DEPRESSION

The paper presents a summary of results considering cholinergic hypothesis on the central processes of human stress response and depression caused by chronic social stress. These studies include both the work of clinicians, who are examining pathogenesis of depression, and experiments with rodents. The authors also consider the history of stress response discovery in humans and vertebrates. The paper analyses the results of early studies (1980s-1990s), which led to the hypothesis on the key role of brain cholinergic system in nonspecific stress response of the whole multicellular organism of humans and rodents. Special attention is paid to the latest ideas on acetylcholine as the most powerful neuromodulator in the brain. Acetylcholine is said to transmit large volumes of information. The authors conducted the summary of experimental and clinical studies showing that the primary reaction of humans and rodents under stress is manifested in the activation of brain cholinergic transmission, but not in subsequent changes in serotonergic system functioning. The paper analyses numerous studies, the result of which confirmed the cholinergic hypothesis on stress and depression. These facts are as follows: firstly, the increase in the acetylcholine level in the brain or in the hippocampus (physostigmine injection) causes similar changes in the behavior and physiological state of rodents under stress; secondly, single-time stress increases the acetylcholine level in several areas of the brain, thus, correlating to adaptive changes in behavior; thirdly, chronic stress that causes disturbances in rodent behavior, which are similar to depression, is accompanied by an increase of the acetylcholine level in the brain. In general, the authors come to the conclusion that ideas on the key role of cholinergic system in stress response can serve as a scientific basis for further research on the depression mechanisms both clinically and experimentally Keywords: stress, depression, acetylcholine, neuromodulator, behavior.

REVISITING THE CHOLINERGIC HYPOTHESIS IN ALZHEIMER’S DISEASE: EMERGING EVIDENCE FROM TRANSLATIONAL AND CLINICAL RESEARCH

Scientific evidence collected over the past 4 decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer’s disease is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the “Cholinergic Hypothesis of AD” and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system as one of several interacting systems failures that contribute to AD pathogenesis.

Enhancing the mind? Memory medicine, dementia, and the aging brain

The study explores the relationship between the neurosciences, aging, anti-aging culture, memory medicine, and the hypercognitive society. The first part traces the discourses of mind from the Enlightenment to contemporary biosocial models where the aging brain has become a social laboratory for research, experimentation, and intervention. The second part explores the Cholinergic Hypothesis, the development of the cholinesterase inhibitors and their recent implementation in cases of Mild Cognitive Impairment (MCI). Critical questions are posed about how the mission to optimize aging has affected projects to enhance the mind.