Project Outline

During healthy ageing, the brain undergoes multi-scale changes to neuronal and network activity. To understand the processes underlying healthy aging, biomarkers are required that can accurately assess brain structure and function. These biomarkers need to be able to determine the degree of brain aging and evaluate the effect of anti-aging interventions. Given recent developments and advances in accessibility of clinical procedures, three main approaches are currently being employed as brain aging biomarkers: measures of cognitive function (functional markers), imaging markers, and body fluids biomarkers. Together these can give an accurate picture of brain age and allow for longitudinal patient studies of healthy ageing.

In our lab, we research early mechanisms of neurodegeneration, primarily focussed on tau pathology. It is well established that tau pathology occurs in the early stages of disease and that a proportion of tau is secreted into cerebral spinal fluid up to 10-15 years prior to the onset of symptoms. We have therefore used CSF (containing high levels of tau) from early Alzheimer’s disease patients as a tool to evaluate the early effects on neuronal and network function. While we have examined the effects of tau, this assay can also be adapted for amyloid, neurofilament light or other appropriate biomarkers.

However, it is intriguing that there are a subset of people who have high amyloid and tau pathology at autopsy and yet never develop cognitive decline or dementia, thus show ‘healthy ageing’. Given that raised tau can also be used as a biomarker for normal brain ageing, in this project we will assess CSF from patients with raised tau but no evidence of cognitive decline to ascertain:

1. Are the forms of tau the same between healthy ageing and in disease?
2. Are there different functional effects of the tau species from healthy people compared to AD patients?
3. Can we use this to determine what is protective in people who maintain healthy ageing despite high tau burden?

This project will combine a molecular biology-based approach to study tau species in CSF and combine this with electrophysiology to understand functional impact. CSF samples will be supplied as part of an ongoing international collaboration.

References

Brown J, Camporesi E, Lantero-Rodriguez J, Olsson M, Wang A, Medem B, Zetterberg H, Blennow K, Karikari TK, Wall M, Hill E. Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations. Acta Neuropathol Commun. 2023 Apr 24;11(1):67. doi: 10.1186/s40478-023-01562-5. PMID: 37095572; PMCID: PMC10127378.

Hill E, Wall MJ, Moffat KG, Karikari TK. Understanding the Pathophysiological Actions of Tau Oligomers: A Critical Review of Current Electrophysiological Approaches. Front Mol Neurosci. 2020 Aug 20;13:155. doi: 10.3389/fnmol.2020.00155. PMID: 32973448; PMCID: PMC7468384.

Techniques

• Whole cell patch clamp electrophysiology
• Extracellular recording
• Immunohistochemistry
• Cell Culture
• Molecular Biology
• Computational Modelling and analysis