Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion As Determinant Factors in Alzheimer's Disease

Overview

Journal J Alzheimers Dis Rep

Publisher IOS Press

Date 2018 Nov 28

PMID 30480234

Citations 36

Authors

Chris J Carter

Affiliations

Soon will be listed here.

Abstract

Diverse pathogens are detected in Alzheimer's disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (, , Bornavirus, , cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, , , ). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to and variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid- autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy.

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