Abstract
Down syndrome (DS) is the primary genetic cause of intellectual disability (ID), which is due to the triplication of human chromosome 21 (HSA21). In addition to ID, HSA21 trisomy results in a number of neurological and physiological pathologies in individuals with DS, including progressive cognitive dysfunction and learning and memory deficits which worsen with age. Further exacerbating neurological dysfunction associated with DS is the concomitant basal forebrain cholinergic neuron (BFCN) degeneration and onset of Alzheimer’s disease (AD) pathology in early mid-life. Recent single population RNA sequencing (RNA-seq) analysis in the Ts65Dn mouse model of DS, specifically the medial septal cholinergic neurons of the basal forebrain (BF), revealed the mitochondrial oxidative phosphorylation pathway was significantly impacted, with a large subset of genes within this pathway being downregulated. We further queried oxidative phosphorylation pathway dysregulation in Ts65Dn mice by examining genes and encoded proteins within brain regions comprising the basocortical system at the start of BFCN degeneration (6 months of age). In select Ts65Dn mice we demonstrate significant deficits in gene and/or encoded protein levels of Complex I-V of the mitochondrial oxidative phosphorylation pathway in the BF. In the frontal cortex (Fr Ctx) these complexes had concomitant alterations in select gene expression but not of the proteins queried from Complex I-V, suggesting that defects at this time point in the BF are more severe and occur prior to cortical dysfunction within the basocortical circuit. We propose dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline onset and specifically linked to BFCN degeneration that may propagate pathology throughout cortical memory and executive function circuits in DS and AD.
Highlights
Down syndrome (DS) is caused by the triplication of human chromosome 21 (HSA21) and is the primary genetic cause of intellectual disability (ID)
To understand changes in oxidative phosphorylation within the basocortical circuit, we examined RNA and protein levels from each of the five complexes in the oxidative phosphorylation pathway from two synaptically connected brain regions critical for attention, memory, and executive function that show a significant decline in DS and Alzheimer’s disease (AD)
This examination was based upon gene expression profile changes in the oxidative phosphorylation pathway from medial septal nucleus (MSN) basal forebrain cholinergic neuron (BFCN) by single population RNA sequencing (RNA-seq) in ∼6 months of age (MO) Ts65Dn mice compared to 2N littermates (Alldred et al, 2021)
Summary
Down syndrome (DS) is caused by the triplication of human chromosome 21 (HSA21) and is the primary genetic cause of intellectual disability (ID). HSA21 triplication is present in approximately 1 in 700 live births and these individuals exhibit multiple systemic functional deficits, including heart conditions, increased incidence of leukemias, epilepsy, premature aging, and neurological deficits (Bittles et al, 2007; So et al, 2007; Lott, 2012; Presson et al, 2013; Mai et al, 2019). Most adults with DS start to exhibit Alzheimer’s disease (AD)-like pathology, including senile plaques, neurofibrillary tangles, synaptic dysfunction, and basal forebrain cholinergic neuron (BFCN) degeneration, with the accompanying cognitive decline, typically by the mid-third decade of life (Mann et al, 1984; Coyle et al, 1988; Beacher et al, 2009; Lott and Dierssen, 2010; Costa, 2012; Lott, 2012; Hartley et al, 2015; Annus et al, 2016). Recent imaging evidence indicates volume reductions in the basal forebrain (BF) predicts entorhinal cortex loss and cortical spread of degeneration in AD and correlates with AD biomarkers (Grothe et al, 2013; Cavedo et al, 2020; Fernández-Cabello et al, 2020; Teipel et al, 2020), suggesting BF dysfunction is one of the earliest pathological changes during the development of AD
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