Parvalbumin Interneuron Regional Variability and Vulnerability in Early Alzheimer's Disease Restricted; Files Only
Goettemoeller, Anne M (Summer 2024)
Abstract
Complex functions performed by the brain require dynamic cortical circuits. Awareness of incoming salient stimuli as well as maintenance of homeostasis require strong regulation of neuronal firing, a phenomenon mediated heavily by inhibitory interneurons. Although typically a strength of the circuit, these imperative interneurons also provide a gateway to circuit chaos should they become vulnerable. Unsurprisingly, many diseases which plague humankind arise from the dysfunction of interneurons. In human patients with Alzheimer’s Disease, one of the earliest observed pathophysiological correlates to cognitive decline is hyperexcitability. The origin of hyperexcitability in early-stage disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type-specific assessments across a multitude of studies, we have observed dysregulation of a subgroup of cortical interneurons, parvalbumin+ (PV) interneurons. We have observed that not only does PV interneuron dysfunction arise prior to severe amyloid pathology, it also arises earliest in regions vulnerable to subsequent amyloid pathology. Furthermore, we note altered PV interneuron firing and circuit hyperexcitability without intrinsic alterations of the expectedly vulnerable excitatory cell type in Layer II of the Lateral Entorhinal Cortex. We suggest this vulnerability is a feature inherent to PV interneurons and may be exacerbated in some cortical regions from a regional-related variability in cell type intrinsic features and protein expression profiles. This study suggests early disease interventions targeting PV interneurons may protect regions with early vulnerability to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.
Table of Contents
Table of Contents
Distribution Agreement
Chapter 1: Introduction
1.1 The Hegemonikon
1.2 Homeostasis of the circuit
1.3 Interneurons and the circuit
1.4 Alzheimer’s Disease
1.5 Vulnerability in Alzheimer’s Disease
1.6 Cell-type-specific assessment of vulnerability
Chapter 2: Methods
2.1 Patch-clamp electrophysiology
2.2 Viral Injections
2.3 RNA expression detection techniques
2.4 Protein expression detection techniques
2.4a Proteomics
2.5 Modeling (By VJO)
2.6 Dynamic Clamp (By VJO)
2.7 Analysis
2.8 Statistics
Chapter 3 : Inhibitory interneuron dysfunction arises in early stages of Alzheimer’s Disease models
3.1 Introduction
3.2 Results
3.3 Discussion
3.4 Supplementary Information
Chapter 4: Native-state proteomics of Parvalbumin interneurons
4.1 Summary
4.2 Introduction
4.3 Results
4.4 Discussion
4.5 Supplementary Information
Chapter 5: Entorhinal Cortex Vulnerability to human APP expression promotes hyperexcitability and tau pathology
5.1 Summary
5.2 Introduction
5.3 Results
5.4 Discussion
5.5 Supplementary Information
Chapter 6: Discussion
6.1 Summary
6.2 Development of PV Interneuron-specific Methods
6.3 Pathophysiology of PV interneurons in AD
6.4 Circuit response to PV Interneuron Dysfunction
6.5 Potential Therapeutic Strategies and Intervention Points for AD
Unpublished Data
Ancillary Documents
Citations
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File download under embargo until 21 February 2025 | 2024-06-25 14:53:10 -0400 | File download under embargo until 21 February 2025 |
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