Window to the brain: a game changer in the discovery of human neuronal circuitry, cellular heterogenicity and biomarker profile indicative of early Alzheimer's disease -related pathology

Introduction

The molecular mechanisms leading to Alzheimer's disease (AD) are poorly understood. This is due to a lack of human tissue samples for research representing early changes of AD pathology. The accumulating pathology, including beta-amyloid and tau proteins, is manifested by concomitant neuroinflammatory reactions geared by malfunctional microglia.

Microglial Subpopulations

Microglia in the human and mouse AD brain exist in various subpopulations, from which a specific, disease-associated microglia population is thought to be involved in AD pathogenesis. However, there is no evidence on whether and how these specific microglial subpopulations actually impair neuronal functions in the human AD brain.

Research Objectives

I will now assess neuron-glia network activities and functions indicative of early AD pathology in humans. I hypothesize that early AD pathology selectively impairs neuronal circuits and that glial cells, especially specific microglia subpopulations, contribute to neuronal dysfunction and cognitive decline.

Biomarker Profile

These events contribute to a detectable vesicle-based biomarker profile in cerebrospinal fluid and blood prior to the clinical disease. Due to early AD pathology present in a subpopulation of idiopathic normal pressure hydrocephalus (iNPH) patients, the brains of the iNPH patients offer a unique window to evaluate cellular and molecular events occurring during early AD.

Methodology

I combine a series of state-of-the-art techniques to answer how and what glial cell subpopulations are associated with altered neuronal network activities at subcellular and spatial resolution in the human brain impacted by early AD-related pathology.

Conclusion

Novel methodologies established in my lab, know-how, and access to unique brain samples make me uniquely positioned to form a holistic view on how early AD pathology impacts cellular functions at multiple levels. This will pinpoint novel molecular targets for further validation and new fluid biomarkers.