title: Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer's disease (AD).
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.
authors.affiliation: LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112, USA ; Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112, USA.
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112, USA ; Department of Ophthalmology, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112, USA ; Department of Neurology, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Lukiw
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)