Biology subjects

McKenzie, C.-A.

Publications and source records attributed to McKenzie, C.-A..

3 recordsLinked to original sources

bioRxiv2023

The remarkable complexity of the brain microbiome in health and disease

Microbes in human brain and their potential contribution to neurodegenerative conditions such as Alzheimers disease (AD) have long been debated. We recently developed a new method (the electronic tree of life, eToL) based on small subunit ribosomal RNA (rRNA) probes, further confirmed by large subunit rRNA analysis, to comprehensively address the spectrum of microorganisms in control and AD brain. We report a remarkable diversity of brain microbes in control brain. The most abundant are fungi, bacteria, and chloroplastida, and we report detailed identification of representative microbial species. The pattern is substantially conserved across different bilateran species from Drosophila to human. In terms of diversity, the human brain microbiome appears to be a subset (~20%) of the gut microbiome. Adenovirus type C was the major virus found in human brain; other viruses were not well represented. However, the spectrum of brain microbes differed between individuals as well as between brain regions examined from single individuals (amygdala, cingulate cortex, hippocampus, hypothalamus); of these four regions, the highest microbial burden was in cingulate cortex. There was evidence of spreading of pathogens between brain regions in single individuals. Some microbes are over-represented in AD brain according to two measures: (i) absolute number of microbes normalized to endogenous human transcripts, and (ii) the number of brain specimens showing overabundance versus control. Species over-represented in AD brain according to both measures notably include bacteria (Streptococcus, Staphylococcus/Bacillus, Sphingomonas/Ralstonia) and fungi (Acrocalymma/Altenaria/Aureobasidium of the Aspergillus group; Komagataella of the Candida group, Cortinarius of the Schizophyllum group, and Tausonia of the Cryptococcus group), that are all related to known human pathogens. In addition, an uncharacterized chloroplastida (algae-related) species was more abundant in AD brain samples. Although these findings point to diverse microbial species, indicative of multiple causation, similar absolute levels of bacteria and fungi in AD brain samples could suggest synergy between pathogens. However, it is important to stress that not all AD samples were positive for these microbes, but this could be because the affected brain region(s) was not examined. These findings support the contention that infection, perhaps associated with declining immunity with age, may contribute to AD development.

neuroscience↗

bioRxiv2019

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Degeneration of synapses in Alzheimers disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in human AD brain. To begin to understand the molecular cascades involved in synapse loss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. Our analysis identified over 5,500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathways including a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling.\n\nHighlightsO_LIProteomic analysis of synapses isolated from Alzheimers disease and control subject brains identifies over 5,500 proteins in human synapses.\nC_LIO_LIIn silico analysis reveals region-specific decreases in proteins involved in synaptic and mitochondrial function and increases in proteins involved in neuroimmune signaling and intracellular signaling in AD.\nC_LIO_LIThe apolipoprotein E4 risk gene is associated with exacerbated changes in synaptic proteins in AD.\nC_LI

neuroscience↗

bioRxiv2018

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimers disease (AD) is the lack of understanding of how amyloid beta (A{beta}) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human taus influence on human A{beta}-induced pathology. We find that A{beta} and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.\n\nHighlights- Expression of human familial Alzheimers associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function.\n- Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.\n- These data suggest that A{beta} and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

neuroscience↗