Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1-42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer's disease.

/pdf/porphyromonas-gingivalis-in-alzheimer-s-disease-brains-1w9io5d5so.pdf

Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

Background Several studies have suggested a population-wide decline in the quality of semen over the past 50 years, but clear evidence of decreasing semen quality in recent decades is lacking. Methods From 1973 through 1992 we measured the volume of seminal fluid, the sperm concentration, and the percentages of motile and morphologically normal spermatozoa in 1351 healthy fertile men. The data on the semen samples were collected at one sperm bank in Paris. The data in each calendar year were analyzed as a function of the year of donation, the age of each patient, the year of birth, and the duration of sexual abstinence before semen collection. Results There was no change in semen volume during the study period. The mean concentration of sperm decreased by 2.1 percent per year, from 89 ×106 per milliliter in 1973 to 60×106 per milliliter in 1992 (P<0.001). During the same period the percentages of motile and normal spermatozoa decreased by 0.6 percent and 0.5 percent per year, respectively (both P<0.001). ...

Decline in Semen Quality Among Fertile Men in Paris During the Past 20 Years

Emerging evidence indicates that gut microbiota is important in the regulation of brain activity and cognitive functions. Microbes mediate communication among the metabolic, peripheral immune, and central nervous systems via the microbiota–gut–brain axis. However, it is not well understood how the gut microbiome and neurons in the brain mutually interact or how these interactions affect normal brain functioning and cognition. We summarize the mechanisms whereby the gut microbiota regulate the production, transportation, and functioning of neurotransmitters. We also discuss how microbiome dysbiosis affects cognitive function, especially in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders.

Alzheimer’s disease (AD) is the most prevalent form of dementia. Despite decades of research following several theoretical and clinical lines, all existing treatments for the disorder are purely symptomatic. AD research has traditionally been focused on neuronal and glial dysfunction. Although there is a wealth of evidence pointing to a significant vascular component in the disease, this angle has been relatively poorly explored. In this review, we consider the various aspects of vascular dysfunction in AD, which has a significant impact on brain metabolism and homeostasis and the clearance of β-amyloid and other toxic metabolites. This may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease. Pathological changes in vessel haemodynamics, angiogenesis, vascular cell function, vascular coverage, blood-brain barrier permeability and immune cell migration may be related to amyloid toxicity, oxidative stress and apolipoprotein E (APOE) genotype. These vascular deficits may in turn contribute to parenchymal amyloid deposition, neurotoxicity, glial activation and metabolic dysfunction in multiple cell types. A vicious feedback cycle ensues, with progressively worsening neuronal and vascular pathology through the course of the disease. Thus, a better appreciation for the importance of vascular dysfunction in AD may open new avenues for research and therapy.

https://www.mdpi.com/2077-0383/8/5/651/pdf

Vascular Dysfunction in Alzheimer's Disease: A Prelude to the Pathological Process or a Consequence of It?

Pathological mechanisms and therapeutic strategies for Alzheimer's disease.

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the vertebrate brain. In the past, there has been a major research drive focused on the dysfunction of the glutamatergic and cholinergic neurotransmitter systems in Alzheimer’s disease (AD). However, there is now growing evidence in support of a GABAergic contribution to the pathogenesis of this neurodegenerative disease. Previous studies paint a complex, convoluted and often inconsistent picture of AD-associated GABAergic remodeling. Given the importance of the GABAergic system in neuronal function and homeostasis, in the maintenance of the excitatory/inhibitory balance, and in the processes of learning and memory, such changes in GABAergic function could be an important factor in both early and later stages of AD pathogenesis. Given the limited scope of currently available therapies in modifying the course of the disease, a better understanding of GABAergic remodeling in AD could open up innovative and novel therapeutic opportunities.

https://www.mdpi.com/1422-0067/18/8/1813/pdf

Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease

Glutamatergic and cholinergic dysfunction are well-attested features of Alzheimer's disease (AD), progressing with other pathological indices of the disorder and exacerbating neuronal and network dysfunction. However, relatively little attention has been paid to the inhibitory component of the excitatory/inhibitory (E/I) network, particularly dysfunction in the gamma-aminobutyric acid (GABA) signaling system. There is growing evidence in support of GABAergic remodeling in the AD brain, potentially beginning in early stages of disease pathogenesis, and this could thus be a valid molecular target for drug development and pharmacological therapies. Several GABAergic drugs have been tested for efficacy in attenuating or reversing various features and symptoms of AD, and this could represent a novel path by which we might address the growing need for more effective and benign therapies.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jnc.14345

The GABAergic system as a therapeutic target for Alzheimer's disease

Sperm DNA integrity is important for fertility, however the incidence of high levels of DNA fragmentation (DNA fragmentation index (DFI) >30%) is not well described. In 2011, our clinics implemente...

https://www.tandfonline.com/doi/pdf/10.1080/19396368.2019.1668077

Chitra Vinnakota

Papers

Towards a Better Understanding of GABAergic Remodeling in Alzheimer’s Disease

Vascular Dysfunction in Alzheimer's Disease: A Prelude to the Pathological Process or a Consequence of It?

The GABAergic system as a therapeutic target for Alzheimer's disease

Incidence of high sperm DNA fragmentation in a targeted population of subfertile men

Vascular dysfunction in Alzheimer’s disease: a biomarker of disease progression and a potential therapeutic target