The antimicrobial protection hypothesis of Alzheimer's disease
10.1016/j.jalz.2018.06.3040
https://www.researchgate.net/publicatio ... 's_disease
Some relevant easier to read articles are at: The paper was relatively readable (at least until my brain filled up). I've quoted a bunch of sections that I found interesting. (There was more, but what I've done is probably overwhelming as is.) The quote heading is my fault, not the authors'.
What Amyloid-beta (Aß)?
Aß is generated by extracellular and intramembrane endoproteolytic cleavage of APP [amyloid-ß precursor protein] ...
The Aß peptide has traditionally been characterized as a functionless byproduct of APP catabolism. This surmise has its origins in the early days of Aß research.
[ ... But research over the last twenty or so years suggests otherwise ...]
Aß has been conclusively demonstrated to be a normal constitutively generated human and animal neuropeptide. Nonetheless, the view that Aß is functionless remains widely held, despite evidence highlighting that the human Aß sequence is 100% conserved across most vertebrate species up to at least 400 million years (humans share Aß42 sequences with coelacanths, an ancient fish taxon) [9]. The absence of an identified physiological role for Aß has led to a widespread view that the peptide’s activities are unfortunate accidents of protein physiochemistry. This, in turn, has helped foster therapeutic strategies aimed at ameliorating AD by eliminating Aß. However, given the emerging findings on the role Aß plays in innate immunity [5,6], there is a clear and urgent need to more carefully assess the dominant model of AD pathogenesis emerging from errant Aß activities that has guided therapeutic strategies for over three decades.
...
Recent evidence strongly suggests that Aß plays a role as an AMP [antimicrobial peptide] in the innate immune system. Comparison of Aß and human cathelicidin antimicrobial peptide (LL-37), an archetypal human AMP, reveals extensive and striking parallels between the two peptides
...
AMPs are the primary effector proteins of the innate immune system. AMPs target bacteria, mycobacteria, enveloped viruses, fungi, protozoans, and, in some cases, transformed or cancerous host cells [22]. AMPs are also potent immunomodulators.
Some thoughts (well, questions) on how APOE4 might relate
How, specifically, might Aß work in the brain?Despite intense study, it remains unclear why expression of APOE-ε4 increases AD risk. Investigations to date have focused on models in which apoE4 is a less effective chaperone than apoE3 or apoE2, leading to reduced peptide clearance and an escalation of Aß activities held to be pathogenic.
...
ApoE is also targeted by pathogens, and apoE4 expression is associated with increased susceptibility to several microbes, including neurotrophic viruses [51]. ... possible roles for apoE4 in AD extend well beyond the poor Aß chaperone model. A fuller understanding of the role apoE plays in Aß-mediated immune pathways may well yield insights into how APOE-ε4 is an important AD risk factor.
Some insights from EO-FAD [early onset familial Alzheimer's disease]The leading model for how Aß may directly kill neurons involves disruption of plasma membranes through the formation of pores or carpet-like structures [63]. This widespread AMP pathway normally mediates killing of microbial cells [63]. It remains unclear why neurotoxic Aß oligomers may target neuronal membranes. AMPs discriminate prokaryotic from eukaryotic host membranes by charge and exhibit a strong specificity for anionic microbial versus zwitterionic host lipid bilayers [32,64,65]. Consistent with an AMP role, Aß normally shows a strong preference for anionic membranes, with soluble oligomers binding more avidly than monomeric peptide [66]. However, Aß is among the 12% to 15% of AMPs that are anionic rather than cationic peptides. AMP-entrapped bacteria secrete proteases that specifically target cationic peptides [67]. Thus, anionic AMPs evade microbial countermeasures aimed at freeing bacteria from AMP-mediated entrapment. However, one disadvantage is that anionic AMPs have reduced avidity for negatively charged microbial membranes. Binding and targeting of microbial membranes by anionic AMPs are typically mediated by positively charged regions that are enriched in cationic residues [67]. Anionic AMPs are also often metaloproteins that bind divalent zinc or copper ions. AMP-bound metal ions form cationic salt bridges with anionic membranes, increasing binding and specificity for microbial cells [67]. Aß is an anionic entrapment AMP and metalloprotein that simultaneously binds Zn11 and Cu11 [68]. Aß-metal binding seems likely to play a role in helping Aß oligomers to discriminate microbes from host cells. Aß oligomerization pathways generate polymorphic oligomeric species with widely differing Zn11 and Cu11 binding activities [68]. For neurotoxic oligomers, metal-mediated targeting of microbial membranes may be limited by how Zn11 and Cu11 are bound, leading to Aß species with increased propensity for binding host cells.
Neuronal membranes are also enriched in negatively charged gangliosides and phospholipid phosphatidylserine [69], which may also contribute to targeting by Aß. Further experimentation will be necessary to validate this model of metal-mediated microbial targeting and its possible involvement in Aß’s neurotoxic activities.
...
The neurotoxic activities of Aß may also include permeabilization of host mitochondrial membranes. Mitochondria are endosymbiotic and retain the anionic membranes of prokaryotes. Mitochondrial membranes are readily bound by Aß, and the peptide has been reported to cause neuronal mitochondria dysfunction [70]. AMP-induced mitophagy and mitochondrial disruption are normal immune pathways that mediate killing of infected and unhealthy host cells. However, dysregulation of these pathways can lead to degenerative pathologies, including vascular disease mediation by the killing of healthy smooth muscle by LL-37 [71]. Understanding that targeting of neuronal mitochondria by Aß may include a normal immune pathway is likely to prompt new models of mitochondrial dysfunction in neurodegeneration. This would include shifting the genesis of Aßmediated mitochondrial dysfunction from intrinsic abnormal activity to dysregulated innate immune pathway.
...
AMPs also play a role in the elaboration of ETs [extracellular traps] through ETosis, a programmed cell death pathway for neutrophils and macrophages/monocytes that occur in response to immunochallenge [75]. ETs entrap microbes in a scaffolding composed of host cellular DNA, histones, and AMPs [76]. ET-entrapped microbes are inactivated by high local AMP and ROS levels generated by the dying host cell [77]. Neutrophil-derived ETs are associated with Aß deposits in AD brain. ... In summary, targeted host cell death can be a deliberate strategy to defeat invaders. Given the wide range of protective pathways mediated by AMP host cytotoxicity, the neurotoxicity of Aß should not be assumed to be intrinsically and exclusively abnormal. Rather, Aß host cytotoxicity may mediate “beneficial suicide” pathways in normal brain. In AD, this activity may become dysregulated, leading to indiscriminate neuronal death. However, it should not be overlooked that Aß may be targeting infected or unhealthy neurons in AD brain. As we discuss later, mounting data link AD etiology with chronic neuroinfections, particularly life-long viral infections. Adaptive immune responses are largely absent from brain. If unchecked, neurons undergoing active viral replication could rapidly spread infection throughout the brain, with lethal consequences. In AD, the neurotoxic actions of Aß may be suppressing potentially serious infection, albeit at high long-term cost.
How might infection increase (or seem to increase) AD risks? Plus, singling out just one bad pathogen isn't going to cut it.Mutations in all three EO-FAD genes, PSEN1, PSEN2, and APP, accelerate Aß deposition by increasing the Aß42:Aß40 ratio, which in turn increases Aß oligomerization. Thus, in terms of the antimicrobial protection hypothesis, EO-FAD mutations can be thought of as leading to the deposition of ß-amyloid, even when not required as an antimicrobial agent.
...
In prevailing AD models, shifts in Aß isoform ratios are considered abnormal perturbations in homeostasis which lead to disease. However, among classical AMPs, shifts in isoform ratios are considered to be part of optimizing protective activities to meet emerging pathogen challenges, albeit sometimes with negative effects for host tissues. AMP isoforms have differing actions, and longer forms often have higher cytotoxicity, whereas shorter species exhibit more immunomodulatory activities [82]. Consistent with this trend, Aß42 appears to be more active than Aß40 against influenza and herpes viruses, bacteria, and C. albicans
...
Thus, shifts in Aß isoform expression may not be exclusively abnormal, and changes in APP processing in normal brain may reflect dynamic fine-tuning by the innate immune system during perceived immune challenge. Sustained shifts in Aß isoform expression, however, may result in AD pathology.
AD pathology leads to degeneration of the integrity of the blood–brain barrier and could increase susceptibility to CNS infection by blood-borne agents. Thus, the infections associated with AD may arise after the onset of the disease. Moreover, no single pathogen has been found to occur in all AD patients. The lack of association between AD and any single pathogen suggests that more than one infectious species may be able to trigger the innate immune response that can lead to Aß deposition.
...
However, given the emerging role innate immunity appears to plays in AD and links between the neuroimmune axis and neuroinflammatory disease, it may be time to give more serious consideration to possible contributions of chronic peripheral infection (potentially including enteric dysbiosis) to AD pathology.
...
It is also possible that no genuine infection is involved in AD pathology, but instead, mistaken perception of infection by the innate immune system mediates the disease.
