Role of Microbes in the Development of Alzheimer's Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco

Abstract

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer's disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by the Chlamydia pneumoniae bacterium, with its potential to use the innate immune system in its spread, and its initiation of tissue damage characteristic of AD. Prof. Fülöp described the role of AD-associated amyloid beta (Aβ) peptide as an antibacterial, antifungal and antiviral innate immune effector produced in reaction to microorganisms that attack the brain. Prof. Barron put forward the novel hypothesis that, according to her experiments, there is strong sequence-specific binding between the AD-associated Aβ and another ubiquitous and important human innate immune effector, the cathelicidin peptide LL-37. Given this binding, LL-37 expression in the brain will decrease Aβ deposition via formation of non-toxic, soluble Aβ/LL-37 complexes. Therefore, a chronic underexpression of LL-37 could be the factor that simultaneously permits chronic infections in brain tissue and allows for pathological accumulation of Aβ. This first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD, from the "amyloid cascade hypothesis," which so far has been quite unsuccessful, to a new "infection hypothesis," or perhaps more broadly, "innate immune system dysregulation hypothesis," which may well permit and lead to the discovery of new treatments for AD patients.

Keywords: Alzheimer’s disease; Chlamydia pneumoniae; HSV-1; LL-37; amyloid beta; infections; innate immunity; spirochetes.

FIGURE 1

Quantification of (A) HSV1 proteins, (B) β-amyloid and (C) abnormal tau phosphorylation in HSV1-infected cells after acyclovir treatment (Wozniak et al., 2011).

FIGURE 2

Senile plaques contain spirochete-specific DNA. Photomicrographs of spirochetal colonies or biofilms in an AD case with confirmed Lyme neuroborreliosis where B. burgdorferi spirochetes were cultivated from the brain. (A) Positive Aβ immunoreaction of senile plaque. (B) Senile plaque of the same AD case, as in (A), exhibiting strong immunoreaction for bacterial peptidoglycan. (C,D) Photomicrographs showing B. burgdorferi antigens in senile plaques immunostained with a polyclonal anti-B. burgdorferi antibody (C) and with a monoclonal anti-OspA antibody (D). (E) B. burgdorferi specific DNA detected by in situ hybridization in senile plaque of an AD patient where ADB1 strain was cultivated. (F) Cortical section of a control case immunostained with a monoclonal anti-OspA antibody showing no immunoreaction. Scale bar A–E: 40 μm, F: 25 μm. Reprinted from Miklossy (2016), with permission from IOS Press.

FIGURE 3

Aβ42 deposits in the CNS at 2 months post-infection following intranasal infection with Chlamydia pneumoniae. Brains were examined by light microscopy for the presence of Aβ42 using a specific anti-Aβ 1–42 antibody. Mag bars = 20 μm (Little et al., 2014).

FIGURE 4

HSV-1-dependent Aβ production in H4 neuroglioma and U118-MG glial cells. (A) H4 neuroglioma cells were cultured in the absence (–) or presence (+) of HSV-1 for 24 h and production of Aβ42 and Aβ40 was quantitated by ELISA assays. (B) Time-course production of Aβ42 and Aβ40 by H4 neuroglioma cells cultured in the presence of HSV-1. (C) Time course of BACE-1 activity in H4 neuroglioma cells exposed to HSV-1 expressed in relative fluorescence units (RFU). (D) Aβ42 and Aβ40 production by U118-MG glioblastoma cells exposed to HSV-1 for 24 h, as determined by ELISA assays. Data are shown as the mean ± SEM of four to five experiments performed in duplicate. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001, ^∗∗∗∗p < 0.0001. Reprinted from Bourgade et al. (2016b), with permission from IOS Press.

FIGURE 5

Binding studies performed by SPRi. The SPRi-chip was functionalized with Aβ40 (t = 0 days) (A,D); Aβ42 (t = 0 days) (B,E) and Aβ42 (t = 24 days) (C, F). All the Aβ peptides were immobilized in replicate (n = 8) on the same SPRi chip at the same concentration (20 μM). SPRi reference-corrected responses related to LL-37 (10 μM) (black) and ovalbumin (10 μM) (gray) (negative control) flowed on the SPRi-chip functionalized with different Aβ forms (A–C). The three SPRi sensograms show the injection of running buffer (baseline) (1), the injection of the analyte (association phase) (2) and the subsequent injection of buffer (dissociation phase) (3). Calibration curve of LL-37 flowed onto different Aβ forms immobilized on the SPRi-chip Aβ40 (t = 0 days, D) Aβ42 (t = 0 days, E), Aβ42 (t = 24 days, F). The equilibrium binding constants (K_A and K_d) values were calculated using a non-linear curve fit of the SPRi response at equilibrium. Reprinted from De Lorenzi et al. (2017), with permission from IOS Press.