Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity

Abstract

The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer’s disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

Unraveling the Role of Antimicrobial Peptides in Insects

“…Moreover, lysozyme binding with Aβ 1-42 in the Drosophila eye was detected, suggesting that such an interaction prevented from the toxic effects of Aβ 1-42 [ 46 ]. Interestingly, antimicrobial activity of the Aβ peptide was reported, suggesting that it is an AMP in the nervous system and that neurodegenerative Alzheimer’s disease may be partially an infectious disease [ 47 ]. Increased activation of innate immunity mechanisms reflected by overexpression of AMP genes was also postulated as a cause of long-term deleterious effects leading to neurological deficits, persistent cell death in brains, and premature aging in a Drosophila model of radiation-induced neurotoxicity.…”

Controversial Properties of Amyloidogenic Proteins and Peptides: New Data in the COVID Era

“…Meanwhile, such data were accumulating and becoming more and more compelling. The antibacterial, antimicrobial, and antiviral activity of amyloidogenic PPs are described in many comprehensive publications [ 45 , 46 , 47 , 48 , 49 , 50 ], so here we will briefly mention only several examples illustrating the antimicrobial and antiviral properties of Aβ and α-synuclein.…”

“…Due to their protective properties, Aβ and its derivatives are considered important and potent natural antimicrobial peptides. They are even called “clinical antibiotics”, which can potentially be developed into clinically useful agents [ 50 , 51 ].…”

An intrinsic network of polar interactions is responsible for binding of UL49.5 C‐degron by the CRL2KLHDC3 ubiquitin ligase

“…3,4 Moreover, epidemiological studies have suggested a link between Alzheimer's disease and HSV-1 infection. [5][6][7] Bovine herpesvirus type 1 (BoHV-1) belongs to the Varicellovirus genus of the Alphaherpesvirinae subfamily and shares a number of biological properties with HSV-1. Numerous varicelloviruses have been identified in animals, including pseudorabies virus in pigs (PRV), equine herpes viruses (EHV-1, EHV-4), feline herpes virus (FHV-1), and canine herpes virus (CHV-1).…”

“…Despite of the skin lesions and blisters, it can cause ocular, gastrointestinal, and esophageal disorders and even encephalitis 3,4 . Moreover, epidemiological studies have suggested a link between Alzheimer's disease and HSV‐1 infection 5–7 …”