Ellingford, R. | Search bioRxiv

bioRxiv2024

Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's Disease

Reduction of amyloid beta (A{beta}) has been shown to be effective in treating Alzheimers Disease (AD), but the underlying assumption that neurons are the main source of pathogenic A{beta} is untested. Here we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of A{beta}, and play a key role in promoting abnormal neuronal hyperactivity in AD. We show that selectively suppressing oligodendrocyte A{beta} production improves AD brain pathology and restores neuronal function in vivo. Our findings suggest that targeting oligodendrocyte A{beta} production could be a promising therapeutic strategy for treating AD.

neuroscience↗

bioRxiv2017

Distinctive Behavioural Anomalies, Structural Brain Phenotypes And Cortical Hyper-Connectivity In Chd8-Deficient Mice

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. To investigate how reduced Chd8 gene dosage may disrupt brain development and predispose individuals to ASD, we generated a Chd8 heterozygous mouse model. In line with clinical observations, we found that Chd8 heterozygous mice displayed subtle brain hyperplasia and hypertelorism, coupled with increased postnatal brain weight. Chd8 heterozygous mice displayed anomalous behaviours, but autism-like social deficits, repetitive and restricted behaviours were not present. Only minor gene expression changes were observed in the embryonic neocortex at E12.5, with more pronounced gene expression changes in postnatal cortex at P5. Differentially expressed genes showed highly significant enrichment for known autism candidates. Amongst the down-regulated transcripts, genes involved in cell adhesion and axon guidance were particularly prominent, implicating impaired connectivity as a potential mechanism underlying the ASD phenotype. To probe this further, we performed resting state functional fMRI and found increased synchronised activity in cortico-hippocampal and auditory-parietal networks, hinting at impaired sensory processing. Together, these data show that Chd8 heterozygous mice recapitulate key clinical features found in patients with CHD8 mutations and show a unique combination of behavioural phenotypes, which may be underpinned by a distinctive disruption of brain connectivity and sensory processing.

neuroscience↗