Microbiome Influence in the Pathogenesis of Prion and Alzheimer’s Diseases

Abstract

Misfolded and abnormal β-sheets forms of wild-type proteins, such as cellular prion protein (PrPC) and amyloid beta (Aβ), are believed to be the vectors of neurodegenerative diseases, prion and Alzheimer’s disease (AD), respectively. Increasing evidence highlights the “prion-like” seeding of protein aggregates as a mechanism for pathological spread in AD, tauopathy, as well as in other neurodegenerative diseases, such as Parkinson’s. Mutations in both PrPC and Aβ precursor protein (APP), have been associated with the pathogenesis of these fatal disorders with clear evidence for their pathogenic significance. In addition, a critical role for the gut microbiota is emerging; indeed, as a consequence of gut–brain axis alterations, the gut microbiota has been involved in the regulation of Aβ production in AD and, through the microglial inflammation, in the amyloid fibril formation, in prion diseases. Here, we aim to review the role of microbiome (“the other human genome”) alterations in AD and prion disease pathogenesis.

APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells

“…The finding that the 37/67 kDa LR may play a key role in Alzheimer's disease [22,23,26] and that it could act as a receptor mediating Aβ cytotoxicity [24,25], prompted us to verify the effects of a specific 37/67 kDa LR inhibitor on the expression levels and posttranslational modifications of APP, which are known to have a critical role in Aβ generation [14,18]. In addition, the correct localization and trafficking of proteins are fundamental for their correct processing and function [17,45].…”

“…Interestingly, deacidification of endosomal/lysosomal system decreases Aβ production [7]. Beside the previously described role of APP endocytosis in Aβ production [8,9], many reports suggest a critical role for intracellular trafficking of APP in Aβ generation [10][11][12][13][14][15][16][17] and indicate the trans-Golgi network as the main sorting station of APP to lysosomes, where the Aβ can be produced [18]. An aberrant production of Aβ in AD brains could amplify its neurotoxic effects through activation of GSK3β (Glycogen synthase kinase 3 beta) [19].…”

Microbiota-Gut-Brain Signaling: A Minireview

“…Butyrate, on the other hand, is generated by bacteria of the phylum Firmicutes (83). Data is accumulating to demonstrate that the gut microbiota influences the perception of pain (84); that it can influence the pathogenesis of Alzheimer's disease (85)(86)(87), Parkinson's disease (88), and some psychiatric disorders (89), such as attention deficit hyperactivity disorder (90) and autism spectrum disorder (91); and that it can be associated with problems of cognitive impairment (92). The relationship between various health problems and activation of the microbiota-gut-brain axis is schematically presented in Fig.…”

Amyloidogenic Peptides in Human Neuro-Degenerative Diseases and in Microorganisms: A Sorrow Shared Is a Sorrow Halved?

“…While some proteins/peptides represent a characteristic hallmark for just one disease, some are also found in various diseases such as hyperphosphorylated Tau protein. Huntingtin (with polyQ tract >33 residues) Huntington's disease Progressively, relevance of microbial commensals came into focus as a possible contributing factor to neurodegenerative disorders (for concise reviews see [10][11][12]). Increasing number of reports provide correlative studies on altered microbiota in those kinds of diseases, but the outcome is quite controversial and evidence-based investigations are still scarce.…”