Selective Expression of Triple Mutant TDP-43 in the Hippocampus Increases Phosphorylate Tau

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 70 to 80% of all cases. The greatest risk factor for AD is aging; an estimated 30 million people are living with AD and over the next 30 years it is projected to increase to over 130 million worldwide. In addition, one in three seniors have died of AD or another dementing disease, and since 2000, deaths from Alzheimer’s disease have increased 89%. TDP-43 is the major pathological protein in motor neuron disease and frontotemporal dementia. Previously, TDP-43 pathology has been reported that in up to 50% of late-onset, sporadic cases of Alzheimer’s disease, the TDP-43 protein has been reported as an age-related co-pathology linked to dementia severity. TDP-43 proteinopathy in those over 80 has recently been recognized as an independent disease entity, limbic- predominant age-related TDP-43 encephalopathy (LATE). There are over one million people living with LATE in the United States. As LATE shares some of the clinical features of dementia seen in AD in addition to co-existing with AD, understanding mechanisms leading to the pathogenesis of LATE and co-morbid TDP-43 pathology could lead to the development of targeted therapeutics. We have developed an inducible cell-specific pathological model by introducing three familial ALS mutations in the human TDP-43 gene(3XTDP43). Utilizing the tetracycline inducible system, we drove 3XTDP43 specifically in the hippocampus (Camk2a-tTA). Ten-month old mice were used in this study where we performed fMRI, histology, Western blot, and solubility fractionations. Results show phosphorylated TDP-43 pathology and a distinct decrease in solubility. In addition, 3XTDP43 overexpression increases phosphorylation of endogenous tau which may indicate aggregation. Though the mice were imaged (fMRI) we have not evaluated those results as of yet. This model may provide a better understanding of the pathogenesis of TDP-43 proteinopathies.