Behavioural deficits and mitochondrial damage in the locus coeruleus neurons in a pseudo phosphorylated human tau rodent model of Alzheimer's disease

Abstract

Early neural abnormality of Alzheimer's disease (AD) involves persistently phosphorylated soluble pre-tangle tau proteins in locus coeruleus (LC) neurons. Cellular toxicity and mitochondrial damage via aggregation of these abnormal tau proteins are thought to induce neurodegeneration early in the progression of AD by compromising metabolic resources in LC neurons. In the current study, behavioural and cognitive functions, along with mitochondrial ultrastructure, were analyzed in a human pre-tangle tau rat model. We infused an adeno-associated viral vector carrying a human tau gene pseudo phosphorylated at 14 sites in 5-month-old TH-Cre rats. Behavioural testing, which took place 10 months post-infusion, showed poorer performance in the spatial and odour discrimination tasks in the pseudo-phosphorylated human tau-infused animals. Following behavioural testing, the animals were perfused, and tissue was embedded for transmission electron microscopy (TEM). Mitochondrial ultrastructural damage was assessed in LC neuronal cell bodies. Results demonstrated a significant increase in mitochondrial damage in the pseudo-phosphorylated human tau-infused rats. These results have the potential to significantly advance our understanding of the early involvement of mitochondrial damage in AD which may lead to earlier detection and potentially, novel therapies for this devastating disease.