Integrative multiomic insights into Alzheimer’s disease pathology
type: CreativeWork
description: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, currently afflicting around 900,000 patients in the United Kingdom. However, therapeutic avenues and factors that can exacerbate AD pathologies remain unclear. Hence, there is an urgent need for a better understanding of AD at the molecular, organellar, cellular, and behavioural levels. Here, I integrated insights from a fruit fly model of AD with data from AD patients. The accumulation of misfolded amyloid-β (Aβ) peptides as plaques is one of the main histopathological hallmarks of AD. In Chapter 3, I analysed the metabolomic changes in flies expressing human Aβ and uncovered alterations in nicotinamide adenine dinucleotide (NAD+) metabolism. NAD+, a component of vitamin B, is essential for both mitochondrial bioenergetics and DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). I found that increasing the bioavailability of NAD+ pharmacologically or by suppressing PARP is neuroprotective in fly models. Using UK Biobank data, I showed that polymorphisms in the human *PARP1* gene or the intake of vitamin B, are associated with a decrease in the risk and severity of Alzheimer’s disease. Building on these observations, I measured PAR levels in flies and found evidence of higher PARP activity. In Chapter 4, I hypothesised that higher PARP is linked to DNA misrepair, and validated this hypothesis in single-nuclei genome sequencing data from AD patients. I observed an imbalance in the nucleotide pool and showed that pharmacological or genetic enhancement of nucleotide metabolism is neuroprotective in AD. In Chapter 5, I conducted a proteomics analysis and revealed significant alterations in one-carbon (1C) metabolism. The 1C pathway facilitates the transfer of methyl groups for biosynthetic pathways and mitochondrial metabolism. I found that enhancing one-carbon metabolism pharmacologically or genetically decreases AD-related impairments in a fly model of AD, and corro…
abstract: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, currently afflicting around 900,000 patients in the United Kingdom. However, therapeutic avenues and factors that can exacerbate AD pathologies remain unclear. Hence, there is an urgent need for a better understanding of AD at the molecular, organellar, cellular, and behavioural levels. Here, I integrated insights from a fruit fly model of AD with data from AD patients. The accumulation of misfolded amyloid-β (Aβ) peptides as plaques is one of the main histopathological hallmarks of AD. In Chapter 3, I analysed the metabolomic changes in flies expressing human Aβ and uncovered alterations in nicotinamide adenine dinucleotide (NAD+) metabolism. NAD+, a component of vitamin B, is essential for both mitochondrial bioenergetics and DNA repair through NAD+-consuming poly (ADP-ribose) polymerases (PARPs). I found that increasing the bioavailability of NAD+ pharmacologically or by suppressing PARP is neuroprotective in fly models. Using UK Biobank data, I showed that polymorphisms in the human *PARP1* gene or the intake of vitamin B, are associated with a decrease in the risk and severity of Alzheimer’s disease. Building on these observations, I measured PAR levels in flies and found evidence of higher PARP activity. In Chapter 4, I hypothesised that higher PARP is linked to DNA misrepair, and validated this hypothesis in single-nuclei genome sequencing data from AD patients. I observed an imbalance in the nucleotide pool and showed that pharmacological or genetic enhancement of nucleotide metabolism is neuroprotective in AD. In Chapter 5, I conducted a proteomics analysis and revealed significant alterations in one-carbon (1C) metabolism. The 1C pathway facilitates the transfer of methyl groups for biosynthetic pathways and mitochondrial metabolism. I found that enhancing one-carbon metabolism pharmacologically or genetically decreases AD-related impairments in a fly model of AD, and corro…
author: Yu, Yizhou
language: eng
keywords: Computational biology, Drosophila, Neurodegeneration
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/44edb471-d52a-4123-a895-f551c74f2d13/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-10-15
date modified: 2026-07-22T22:24:31Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.106816