Characterising metabolic deficits in sporadic and familial Alzheimer’s disease to identify new therapeutic targets

Introduction: Alzheimer’s disease (AD) is the most common form of dementia with amyloid and tau aggregation central to disease pathology. Mitochondrial function and glycolysis changes are seen early in the disease. Understanding metabolic changes in the nervous system and peripherally will help develop new AD therapies. This thesis investigates how metabolism in peripheral patient fibroblasts and astrocytes derived from these fibroblasts is affected in AD and its therapeutic and biomarker potential. Methods: Fibroblasts were taken from sporadic or familial (Presenilin 1 mutation) AD patients and controls. Mitochondrial structure, function, and glycolysis was assessed. The same fibroblasts were reprogrammed into induced neuronal progenitor cells and subsequently astrocytes. Mitochondrial and glycolytic function was assessed in the astrocytes. Metabolic changes were correlated with clinical features of AD and astrocytes were treated with drugs known to improve mitochondrial function. Results: Sporadic fibroblasts had a more interconnected mitochondrial network, lower mitochondrial membrane potential and lower mitochondria spare respiratory capacity (MSRC). Similar changes were seen in familial fibroblasts but MSRC was not reduced. Sporadic and familial AD astrocytes had reductions in total ATP, reduced MSRC, and a more interconnected mitochondrial network. Apoε4/4 phenotype worsened ATP deficits in sporadic fibroblasts and astrocytes. MSRC correlated with clinical markers of AD in both sporadic astrocytes and fibroblasts. Deficits in total ATP and mitochondrial structure were partially corrected by treatment with known mitochondrial enhancers. Discussion: This thesis is one of the first to show that metabolic deficits in both astrocytes and fibroblasts correlate with clinical features of AD. It highlights that astrocytes from sporadic and familial AD patients have impaired metabolism, which can be corrected, and potentially used as a biomarker of the future. This thesis has shown the importance of studying metabolism in AD, and further highlights astrocyte metabolism as potentially a key factor in the development of AD.