Hippocampal neurobiology and function in an aged mouse model of TDP-43 proteinopathy in an APP/PSEN1 background

• Published in: Neuroscience letters 2021-07, Vol.758, p.136010-136010, Article 136010
• Main Authors: Arezoumandan, Sanaz, Cai, Xuezhu, Kalkarni, Praveen, Davis, Stephani A., Wilson, Katherine, Ferris, Craig F., Cairns, Nigel J., Gitcho, Michael A.
• Format: Article
• Language: English
• Subjects: Aging - pathology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer’s disease; Amygdala - diagnostic imaging; Amygdala - pathology; Amygdala - physiology; Amyloid beta-Protein Precursor - genetics; Animals; Brain Mapping; Disease Models, Animal; DNA-Binding Proteins - genetics; Female; Hippocampus - diagnostic imaging; Hippocampus - pathology; Hippocampus - physiopathology; Humans; Limbic predominant age-related TDP-43 encephalopathy (LATE); Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Network connectivity; Presenilin-1 - genetics; Resting state BOLD functional connectivity; TDP-43; TDP-43 Proteinopathies - genetics; TDP-43 Proteinopathies - pathology; TDP-43 Proteinopathies - physiopathology
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2021.136010

•Survival reduced in mice expressing human TDP-43 in an APP/PSEN1 background.•Significant neuronal loss and plaques reduced in TDP-43/APP/PSEN1 expressing mice.•TDP-43/APP/PSEN1 mice show loss of functional coupling in hippocampus and amygdala.•End of life study reveals some tumors evident regardless of genotype. Aging is a major risk factor for Alzheimer’s disease (AD), the most common cause of dementia worldwide. TDP-43 proteinopathy is reported to be associated with AD pathology is almost 50% of cases. Our exploratory study examined near end-stage (28 months old) mice selectively driving expression of human TDP-43 in the hippocampus and cortex in an APP/PSEN1 background. We hypothesized that hippocampal neuropathology caused by β-amyloidosis with TDP-43 proteinopathy induced in this model, resembling the pathology seen in AD cases, manifest with changes in resting state functional connectivity. In vivo magnetic resonance imaging and post-mortem histology were performed on four genotypes: wild type, APP/PSEN1, Camk2a/TDP-43, and Camk2a/TDP-43/APP/PSEN1. Our results revealed loss of functional coupling in hippocampus and amygdala that was associated with severe neuronal loss in dentate gyrus of Camk2a/TDP-43/APP/PSEN1 mice compared to APP/PSEN1 and wild type mice. The loss of cells was accompanied by high background of β-amyloid plaques with sparse phosphorylated TDP-43 pathology. The survival rate was also reduced in Camk2a/TDP-43/APP/PSEN1 mice compared to other groups. This end-of-life study provides exploratory data to reach a better understanding of the role of TDP-43 hippocampal neuropathology in diseases with co-pathologies of TDP-43 proteinopathy and β-amyloidosis such as AD and limbic predominant age-related TDP-43 encephalopathy (LATE).