Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.
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http://dx.doi.org/10.3389/fnagi.2018.00224 | DOI Listing |
J Biol Chem
February 2023
Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan, USA. Electronic address:
The Saccharomyces cerevisiae Yta7 is a chromatin remodeler harboring a histone-interacting bromodomain (BRD) and two AAA+ modules. It is not well understood how Yta7 recognizes the histone H3 tail to promote nucleosome disassembly for DNA replication or RNA transcription. By cryo-EM analysis, here we show that Yta7 assembles a three-tiered hexamer with a top BRD tier, a middle AAA1 tier, and a bottom AAA2 tier.
View Article and Find Full Text PDFJ Environ Manage
February 2022
Department of Civil Engineering, Lassonde School of Engineering, York University, ON, M3J1P3, Canada. Electronic address:
The interest in the A-stage of the adsorption/bio-oxidation (A/B) process has considerably increased due to its capacity of carbon redirection to the solids stream. Induced by its flexible and compact design, the Alternating Activated Adsorption (AAA) was recently implemented in full-scale as an alternative A-stage system. However, the literature on such a system is scarce.
View Article and Find Full Text PDFCell Rep
June 2019
Department of Crystallography, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK. Electronic address:
AAA+ proteins form asymmetric hexameric rings that hydrolyze ATP and thread substrate proteins through a central channel via mobile substrate-binding pore loops. Understanding how ATPase and threading activities are regulated and intertwined is key to understanding the AAA+ protein mechanism. We studied the disaggregase ClpB, which contains tandem ATPase domains (AAA1, AAA2) and shifts between low and high ATPase and threading activities.
View Article and Find Full Text PDFElife
November 2018
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
The biogenesis of 60S ribosomal subunits is initiated in the nucleus where rRNAs and proteins form pre-60S particles. These pre-60S particles mature by transiently interacting with various assembly factors. The ~5000 amino-acid AAA+ ATPase Rea1 (or Midasin) generates force to mechanically remove assembly factors from pre-60S particles, which promotes their export to the cytosol.
View Article and Find Full Text PDFJ Biol Chem
December 2018
From the Department of Biology, Faculty of Science and Engineering and
ClpB, a bacterial homologue of heat shock protein 104 (Hsp104), can disentangle aggregated proteins with the help of the DnaK, a bacterial Hsp70, and its co-factors. As a member of the expanded superfamily of ATPases associated with diverse cellular activities (AAA), ClpB forms a hexameric ring structure, with each protomer containing two AAA modules, AAA1 and AAA2. A long coiled-coil middle domain (MD) is present in the C-terminal region of the AAA1 and surrounds the main body of the ring.
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