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

Carter, Chris J.

The antimicrobial effects of A␤ are blocked by an antibody to this peptide [48] . A number of studies have reported the presence of autoantibodies to A␤ in the serum of the elderly [197] and in AD [198, 199] . They are also observed in mild cognitive impairment patients with higher plasma levels in those who progressed to AD [200] . Serum and CSF levels of antigen-bound A␤-autoantibodies were found to be significantly higher in AD patients compared to age and gender-matched control subjects [201] . It has been suggested that these autoantibodies may well be derived from antibodies raised to pathogens via antigen mimicry. Among the many pathogen proteins showing sequence homology to antigenic regions of A␤ are those from B. burgdorferi, C. Neoformans, C. pneumoniae, H. pylori, P. gingivalis, and herpes viruses (HSV1, HHV6, and the cytomegalovirus) [80, 202] . Cross-reactivity between antibodies to HSV-1 and synuclein (another antimicrobial peptide [160] ) has also been experimentally demonstrated [203] . Regardless of the origin of these autoantibodies, their potential to attenuate the antimicrobial effects of A␤ could well contribute to systemic pathogen accumulation, thus rendering cerebral entry more likely. It has already been suggested that A␤ might be used as a therapeutic antibiotic agent [204] . By the same criteria, the removal of blood-borne A␤ autoantibodies by immunoadsorption, to restore such potential, might be considered as a therapeutic option in AD. Autoantibodies to the alpha1-adrenergic receptor may also play a pathological role in relation to the AD vasculature and their immunoadsorption has resulted in a stabilization of cognitive and mental condition in a small group of AD patients [205] .