Investigation of Metabolic Dysfunction in Alzheimer’s Patient iPSC-derived Neuron and Astrocytic Cells

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, affecting an estimated 44million people worldwide. Currently, there are no methods available for the definitive diagnosisor treatment of AD before the onset of the overt clinical features of the disease. AD isassociated with the formation of amyloid plaques and NFTs formed as a result of theaccumulation of Aβ and abnormally folded tau proteins. Metabolic dysfunction has beenrecognised as a preclinical pathogenic event preceding obvious clinical onset of AD bydecades. The aim of this project was to determine if metabolic dysfunction correlates withexposure to Aβ peptides. Our hypothesis is that early metabolic dysfunction occurs in ADbefore the onset of symptoms, and is related to excessive production of toxic Aβ species.Neurons and astrocytes were differentiated from hiPSC-derived NPCs; ‘healthy’ and familialAD (fAD) patients. ‘Healthy’ cells were exposed to synthetic Aβ1-42 oligomers and thenglucose uptake and glycogen storage was determined. Exposure to synthetic Aβ1-42 induceda significant reduction in glucose uptake in ‘healthy’ hiPSC-derived astrocytes and neurons aswell as primary human astrocytes (HA). A significant reduction in glycogen storage was alsorecorded for the ‘healthy’ hiPSC-derived astrocytes, but not in HA. To determine if neuronsand astrocytes from fAD patient-derived hiPSC demonstrated metabolic dysfunction, glucoseuptake and glycogen storage was determined in these cells. Human fAD patient iPSC-derivedastrocytes and neurons demonstrated increased Aβ production compared to ‘healthy’ controls.These cultures also demonstrated reduced glucose uptake. However, the conditioned mediafrom the fAD cultures failed to induce metabolic dysfunction in ‘healthy’ control cells. Theseresults provide evidence of early metabolic dysfunction in human fAD, and provide animportant step in understanding the role of Aβ early in the progression of AD.

Date of Award	2020
Original language	English
Supervisor	Eric J Hill (Supervisor) & James Brown (Supervisor)