Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer's disease (AD) - PubMed (original) (raw)

Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer's disease (AD)

Yuhai Zhao et al. J Nat Sci. 2015 Jul.

Abstract

According to the 'amyloid cascade hypothesis of Alzheimer's disease' first proposed about 16 years ago, the accumulation of Aβ peptides in the human central nervous system (CNS) is the primary influence driving Alzheimer's disease (AD) pathogenesis, and Aβ peptide accretion is the result of an imbalance between Aβ peptide production and clearance. In the last 18 months multiple laboratories have reported two particularly important observations: (i) that because the microbes of the human microbiome naturally secrete large amounts of amyloid, lipopolysaccharides (LPS) and other related pro-inflammatory pathogenic signals, these may contribute to both the systemic and CNS amyloid burden in aging humans; and (ii) that the clearance of Aβ peptides appears to be intrinsically impaired by deficits in the microglial plasma-membrane enriched triggering receptor expressed in microglial/myeloid-2 cells (TREM2). This brief general commentary-perspective paper: (i) will highlight some of these very recent findings on microbiome-secreted amyloids and LPS and the potential contribution of these microbial-derived pro-inflammatory and neurotoxic exudates to age-related inflammatory and AD-type neurodegeneration in the host; and (ii) will discuss the contribution of a defective microglial-based TREM2 transmembrane sensor-receptor system to amyloidogenesis in AD that is in contrast to the normal, homeostatic clearance of Aβ peptides from the human CNS.

Keywords: Alzheimer’s disease (AD); Aβ42 peptides; amyloidogenesis; beta amyloid precursor protein (βAPP); hologenome; inflammation; innate-immunity; senile (amyloid) plaques (SP); triggering receptor expressed in microglial/myeloid cells-2 (TREM2).

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Conflict of interest statement

Conflict of interest: No conflicts declared.

Figures

Figure 1

Figure 1. Highly schematicized depiction of the potential contribution of gastrointestinal (GI) tract microbiome-derived amyloids and lipopolysaccharide (LPS) to systemic and/or CNS amyloid burden – as

the major component if the human microbiome, gastrointestinal (GI) tract microbial sources of amyloid, LPS and/or other microbial-derived signaling molecules have potential to contribute to both systemic amyloid and CNS amyloid burden in their respective CNS compartments. The other major source of CNS amyloid – Aβ40 and Aβ42 peptide monomers (small red circles) – is generated from the tandem beta- and gamma-secretase (β- and γ-secretase; red and purple ovals, respectively) mediated cleavage of the neuronal cell plasma membrane-resident beta-amyloid precursor protein (βAPP, orange oval, lower left panel). The amyloid contribution from the microbiome may be increasingly important during the course of aging when both the GI tract barrier and blood-brain barrier become significantly more permeable to small molecules. Amyloidogenesis is further promoted, and phagocytosis and Aβ42 peptide clearance impaired, by insufficient TREM2 (green oval, right panel), a microglial cell plasma membrane receptor-sensor whose down-regulation has been shown to be mediated by increases in reactive oxygen species (ROS), NF-kB and miRNA-34a signaling. TREM2 function is linked to the TYROBP (DAP12) transmembrane protein (brown oval, right panel) whose abundance in unchanged in AD [–54]. These or related mechanisms may operate (i) directly, via LPS/amyloid leakage through compromised GI tract or blood-brain barriers; (ii) directly, through deficits in the sensor/receptor TREM2; and/or (iii) indirectly, through LPS/amyloid-triggered cytokines or other small pro-inflammatory molecules which transit normally protective physiological barriers. Interestingly, microbes and their secretory exudates are extremely powerful pro-inflammatory and innate-immune system activators – gaining free access to the CNS would further induce these complement proteins and inflammatory cytokines which subsequently enhance vascular permeability, trigger host immunogenicity, and further induce the generation of ROS and NF-kB signaling. These neuropathogenic signals further promote amyloid aggregation and inflammatory degeneration characteristic of age-related neurological diseases including AD and other neurological disorders that exhibit defective Aβ42 peptide clearance mechanisms and progressive amyloidogenesis [–, –63]. See text for further details.

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