Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer’s Disease

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.

Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome

“…Similar to DS, in the TS mouse, these alterations are aggravated throughout life by a variety of neuropathological processes, including increased OS [ 37 , 38 , 39 ]. In fact, TS mice exhibit an oxidative and mitochondrial brain dysfunction profile similar to the one previously described in humans with DS [ 36 , 37 , 38 , 44 , 45 , 46 , 47 , 48 ]. The increase in OS in TS mice has also been related to (i) impairments of the UPS and autophagy [ 27 , 49 ], (ii) the high density of cells with a senescent phenotype [ 35 , 39 , 46 ], and (iii) the premature neurodegeneration that occurs in the brain of this model starting at the age of 6 months [ 44 , 48 , 50 ].…”

“…OS reported in DS results from an imbalance between ROS production and the antioxidant system response. Previous studies from our and other laboratories have demonstrated that the hippocampus of the TS mouse is particularly vulnerable to persistent OS [ 38 , 46 , 48 ]. To better understand the hippocampal OS status of adult TS mice, first, we evaluated ROS production in both groups of animals using an H2DCFDA assay on hippocampal homogenates.…”

Temporal and brain region‐specific elevations of soluble Amyloid‐β40‐42 in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease

“…Mice were weighed, anesthetized via intraperitoneal injection of ketamine (120 mg/kg body weight) and xylazine (6 mg/kg), and then transcardially perfused with phosphate‐buffered saline. After recording post‐mortem brain weight, we dissected the basal forebrain in the medial septal/ventral diagonal band region as described previously (Alldred et al, 2021) by taking an approximately 1.5 mm thick coronal section at approximately Bregma 1.35–0.26, between the rostral‐most appearance of the anterior forceps of the corpus callosum and where the anterior commissure crosses midline (Figure 6). Frontal cortex samples were collected bilaterally from directly above the basal forebrain; hippocampal, cortical, and cerebellar tissue were isolated bilaterally from the remainder of the brain.…”

Basal forebrain cholinergic neurons are vulnerable in a mouse model of Down syndrome and their molecular fingerprint is rescued by maternal choline supplementation

“…[106][107][108] Glucuronidase Beta (GusB; Mm01197698_m1) qRT-PCR products were utilized as a control, as GusB did not show significant changes in RNA-seq data obtained from BFCNs herein or in previous analyses. 52,104,105 Negative controls consisted of the reaction mixture without input RNA. Sample data was compared with respect to PCR product synthesis for each gene tested.…”