Investigation of Cell-type-specific Molecular Changes in Physiological and Pathophysiological Ageing of the Human Brain
Muralidharan, Chandramouli LU
(2026)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Ageing in the human brain is a major risk factor for most neurodegenerative diseases. Yet the cell-type-specific molecular changes that contribute to this risk remain poorly understood. This thesis investigates cell-type-specific changes across multiple levels of molecular regulation and their roles in physiological and pathophysiological brain ageing.
Using single-nucleus RNA sequencing of postmortem tissue, transcriptomic ageing clocks were developed to measure the progression of ageing at a cell-type-specific level (Paper I). The clocks could additionally predict accelerated ageing in distinct cell types under pathophysiological conditions such as Alzheimer’s disease and schizophrenia, highlighting their utility in identifying... (More) - Ageing in the human brain is a major risk factor for most neurodegenerative diseases. Yet the cell-type-specific molecular changes that contribute to this risk remain poorly understood. This thesis investigates cell-type-specific changes across multiple levels of molecular regulation and their roles in physiological and pathophysiological brain ageing.
Using single-nucleus RNA sequencing of postmortem tissue, transcriptomic ageing clocks were developed to measure the progression of ageing at a cell-type-specific level (Paper I). The clocks could additionally predict accelerated ageing in distinct cell types under pathophysiological conditions such as Alzheimer’s disease and schizophrenia, highlighting their utility in identifying selective vulnerability. At the post-translational level, the underexplored phosphoproteome of Huntington’s disease was profiled in a neuronal context using patient-derived induced neurons (Paper II). The analysis revealed dysregulated components of key homeostatic cell signalling pathways, including autophagy, and identified potential therapeutic targets. To further improve in vitro induced neuronal models, direct neuronal conversion of an alternative, accessible somatic cell source sharing developmental lineage with neurons was established (Paper III). Dental pulp stem cells, isolated from the dental pulp of extracted third molars, were converted into induced neurons (iNs) with superior efficiency compared to dermal fibroblasts, strongly indicating the influence of cell lineage on direct reprogramming.
Individually, each contribution addresses a specific gap in the field. Collectively, they reflect a broader effort to study human brain ageing with greater resolution, across multiple molecular levels, and in more physiologically relevant human cellular contexts. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3557b944-84db-45df-9c78-ae8f6d5bb8d5
- author
- Muralidharan, Chandramouli
LU
- supervisor
-
- Karolina Pircs LU
- Johan Jakobsson LU
- Yogita Sharma LU
- opponent
-
- Associate Professor Mertens, Jerome, Department of Neurosciences, University of California San Diego, La Jolla, California, USA
- organization
- publishing date
- 2026
- type
- Thesis
- publication status
- published
- subject
- keywords
- Ageing, Neurodegeneration, Ageing Clocks, Brain Ageing, Transcriptomic Ageing Clocks, Single-cell Ageing clocks, Direct reprogramming, Direct neuronal conversion, Induced Neurons, Huntington’s Disease, Dental Pulp Stem Cells, Phosphoproteomics, Multi-omics, Single-nuclei RNA sequencing
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2026:53
- pages
- 78 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/64227806272
- defense date
- 2026-04-24 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-851-1
- language
- English
- LU publication?
- yes
- id
- 3557b944-84db-45df-9c78-ae8f6d5bb8d5
- date added to LUP
- 2026-03-30 17:23:02
- date last changed
- 2026-04-01 12:42:13
@phdthesis{3557b944-84db-45df-9c78-ae8f6d5bb8d5,
abstract = {{Ageing in the human brain is a major risk factor for most neurodegenerative diseases. Yet the cell-type-specific molecular changes that contribute to this risk remain poorly understood. This thesis investigates cell-type-specific changes across multiple levels of molecular regulation and their roles in physiological and pathophysiological brain ageing. <br/>Using single-nucleus RNA sequencing of postmortem tissue, transcriptomic ageing clocks were developed to measure the progression of ageing at a cell-type-specific level (Paper I). The clocks could additionally predict accelerated ageing in distinct cell types under pathophysiological conditions such as Alzheimer’s disease and schizophrenia, highlighting their utility in identifying selective vulnerability. At the post-translational level, the underexplored phosphoproteome of Huntington’s disease was profiled in a neuronal context using patient-derived induced neurons (Paper II). The analysis revealed dysregulated components of key homeostatic cell signalling pathways, including autophagy, and identified potential therapeutic targets. To further improve in vitro induced neuronal models, direct neuronal conversion of an alternative, accessible somatic cell source sharing developmental lineage with neurons was established (Paper III). Dental pulp stem cells, isolated from the dental pulp of extracted third molars, were converted into induced neurons (iNs) with superior efficiency compared to dermal fibroblasts, strongly indicating the influence of cell lineage on direct reprogramming.<br/>Individually, each contribution addresses a specific gap in the field. Collectively, they reflect a broader effort to study human brain ageing with greater resolution, across multiple molecular levels, and in more physiologically relevant human cellular contexts.}},
author = {{Muralidharan, Chandramouli}},
isbn = {{978-91-8021-851-1}},
issn = {{1652-8220}},
keywords = {{Ageing; Neurodegeneration; Ageing Clocks; Brain Ageing; Transcriptomic Ageing Clocks; Single-cell Ageing clocks; Direct reprogramming; Direct neuronal conversion; Induced Neurons; Huntington’s Disease; Dental Pulp Stem Cells; Phosphoproteomics; Multi-omics; Single-nuclei RNA sequencing}},
language = {{eng}},
number = {{2026:53}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Investigation of Cell-type-specific Molecular Changes in Physiological and Pathophysiological Ageing of the Human Brain}},
url = {{https://lup.lub.lu.se/search/files/246202477/Chandramouli_Muralidharan_-_WEBB.pdf}},
year = {{2026}},
}