Parvalbumin Interneuron Dysfunction as Driver of Tau Pathology in Early Alzheimer’s Disease Restricted; Files Only

Abstract

Cortical circuit stability depends on tightly regulated interactions between excitatory and inhibitory neurons. Among inhibitory cell types, parvalbumin-positive (PV) interneurons are central to maintaining this balance, and their dysfunction is increasingly implicated in the early stages of Alzheimer’s Disease (AD). Hyperexcitability in the entorhinal cortex (EC) is one of the earliest physiological hallmarks of AD, but the underlying mechanisms remain incompletely understood. Across this dissertation, we examined how PV interneuron activity contributes to early circuit disruption and drives the progression of tau pathology in AD. We found that expression of human amyloid precursor protein (hAPP) in the EC selectively impairs PV interneuron function, leading to local hyperexcitability in the absence of intrinsic dysfunction in excitatory neurons. This effect was specific to humanized amyloid-β and could not be replicated with murine APP. In a complementary set of experiments in the EC, we showed that excitatory neurons that developed large tau aggregates exhibited reduced intrinsic excitability, while PV interneurons were relatively resistant to tau accumulation and excitability changes. Critically, we found that PV interneuron activity regulated tau hyperphosphorylation in neighboring excitatory neurons in vivo. Chemogenetic inhibition of PV cells increased hyperphosphorylated tau levels, while enhancing PV activity attenuated tau pathology, even in the presence of hAPP overexpression, emphasizing the importance of inhibitory tone in modifying disease progression. Further, we observed spread of pathological tau into the dorsal hippocampus, including dentate granule cells (DGCs), following AAV-mediated tau expression in the distal EC. In response, we developed and validated a Cre-independent enhancer-AAV strategy that selectively targets DGCs in wild-type mice, providing a new tool for precise genetic access to this vulnerable population. Altogether these studies identify PV interneurons as both early targets and modulators of AD-related pathology and introduce a novel, translational approach for circuit-level intervention during early disease stages.

Table of Contents

Chapter 1: Introduction................................................................................................................ 1

1.1 The excitatory-inhibitory balance..................................................................................2

1.2 Clinically staged biomarkers of Alzheimer’s disease....................................................3

1.3 Circuit hyperexcitability in early Alzheimer’s disease..................................................7

1.4 Vulnerability of Entorhinal Cortex in early Alzheimer’s disease..................................8

1.5 The relationship between circuit hyperexcitability and pathological tau.................... 10

Chapter 2: Methods..................................................................................................................... 15

2.1 Animals........................................................................................................................16

Adeno-associated viral (AAV) vectors........................................................................ 16

Viral injections.............................................................................................................19

2.2 Ex vivo slice electrophysiology....................................................................................20

Acute slice preparation................................................................................................ 20

Whole-cell patch clamp recordings............................................................................. 21

2.3 Chemogenetics.............................................................................................................22

2.4 Histology......................................................................................................................24

Fluorescent in situ hybridization (RNAscope)................................................................ 24

Immunohistochemistry................................................................................................ 25

Immunofluorescence....................................................................................................26

2.5 Analysis........................................................................................................................28

RNAscope experiments............................................................................................... 28

Whole-cell patch clamp experiments...........................................................................28

Immunofluorescence experiments............................................................................... 29

2.6 Statistics.......................................................................................................................32

Chapter 3: Human APP expression in the Entorhinal Cortex induces parvalbumin

interneuron dysfunction and accelerates tau pathology...........................................................34

3.1 Summary......................................................................................................................35

3.2 Introduction..................................................................................................................36

3.3 Results..........................................................................................................................37

3.4 Discussion....................................................................................................................55

3.5 Supplementary Information......................................................................................... 60

Chapter 4: Restoring inhibitory tone: Chemogenetic enhancement of parvalbumin

interneurons attenuates APP-induced tau pathology...............................................................74

4.1 Summary......................................................................................................................75

4.2 Introduction..................................................................................................................76

4.3 Results..........................................................................................................................78

4.4 Discussion....................................................................................................................97

4.5 Supplemental Information......................................................................................... 106

Chapter 5: Downstream Impacts: Development of an enhancer-AA V strategy to selectively

target dentate granule cells....................................................................................................... 121

5.1 Summary....................................................................................................................122

5.2 Introduction................................................................................................................122

5.3 Results........................................................................................................................125

5.4 Discussion..................................................................................................................137

5.5 Supplementary Information....................................................................................... 142

Chapter 6: Discussion................................................................................................................147

6.1 Conclusions summary................................................................................................148

6.2 Differential vulnerability of excitatory neurons and PV interneurons to

pathophysiological effects of hyperphosphorylated tau.................................................. 149

6.3 The effect of human APP-induced hyperexcitability on hyperphosphorylated tau in

early AD models.............................................................................................................. 151

6.4 Development of enhancer-AAV method selectively targeting dentate granule cells.153

6.5 Possible therapeutic approaches and intervention opportunities for AD...................154

Unpublished Data...................................................................................................................... 157

Citations......................................................................................................................................162

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Molecular Biology, Neuroscience Biology, Cell
Keyword	Dentate granule cells Entorhinal cortex Tau pathology Amyloid precursor protein Parvalbumin interneurons adeno-associated viruses Chemogenetics Circuit hyperexcitability Tau phosphorylation Intrinsic excitability Alzheimer's disease AAVs
Committee Chair / Thesis Advisor	Dr. Matthew J.M. Rowan, Emory University
Committee Members	Dr. Katharine E. McCann, Georgia Institute of Technology Dr. Peter Wenner, Emory University Dr. James Q. Zheng, Emory University

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