Alzheimer's disease (AD) is the most common form of dementia and the sixth leading cause of death in the U.S. that affects 5.7 million Americans. There is no cure for AD and it has been 15 years since the latest AD drug, Memantine, was approved by the FDA. Remarkably, AD patients show fluctuations of cognitive function in the course of hours or days. This behavior cannot be explained by the sudden loss or gain of neurons, neurofibrillary tangles or beta-amyloid plaques. Instead, lucid moments experienced by AD patients likely represent emergence of normal neuronal network activity that is disrupted by pathological events in the AD brain. In both AD patients and mouse models of AD, neuronal network hypersynchrony (epileptiform discharges and seizures) and altered oscillatory network activity (brain rhythms) are observed. Recent discoveries show that inhibitory interneuron dysfunction is a key upstream mechanism leading to network hypersynchrony, decreased behavior-dependent gamma oscillatory power and impaired cognitive function in the J20 model of AD. Deficits in inhibitory interneurons are found in both AD patients and mouse models of AD where levels of the voltage-gated sodium channel subunit Nav1.1 are decreased in the parietal cortex. Nav1.1 is predominantly expressed in the parvalbumin (PV)-positive inhibitory interneurons, which generate gamma oscillatory activity that increases during sensorimotor and cognitive. PV interneurons are critical in modulating cognition-associated gamma oscillatory activity, however, the in vivo functional deficits of PV interneurons and how PV interneurons contribute to disrupted gamma rhythms and network hypersynchrony in AD is unknown. Using in vivo two-photon imaging, electroencephalogram (EEG) recordings and behavioral assessments, the relationship between in vivo PV cell activity and altered gamma oscillations in behaving head-fixed J20 mice will be determined (Aim 1). Furthermore, Long-term EEG recordings will help to dissect the role of PV interneurons in brain-state- and disease-state-dependent network hypersynchrony (Aim 2). Completion of the first two aims during the mentored phase of this award will allow the full development of an innovative technique, which enables a new research direction towards the interaction of inhibitory interneurons with other cell types in the brain to determine the cause and effect of interneuron dysfunction in AD. During the independent phase of this award, Aim 3 investigates how in vivo dysfunction of PV interneurons causes dysregulation of excitatory neuron activity contributing to altered oscillatory activity and network hypersynchrony in J20 mice. Genetic Nav1.1 overexpression will be used to modulate PV cell function to gain further mechanistic insight in all three aims. The long-term goal is to understand how inhibitory interneurons modulate oscillatory rhythms in the brain to alter cognitive function. This mechanistic insight could potentially lead to improvement of cognitive function in AD patients by manipulating inhibitory interneurons and network function, similar to AD patients having lucid moments, irrespective of other pathologies in the brain.

Public Health Relevance

Alzheimer's disease is the most common form of dementia and the sixth leading cause of death in the U.S., but this devastating disease has no cure. Currently, 5.7 million Americans are living with Alzheimer's disease and 1 in 3 seniors die from dementia, which is more than breast cancer and prostate cancer combined. This research will reveal novel insights on the functional abnormalities of neurons that underlie cognitive impairment in Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Career Transition Award (K99)
Project #
1K99AG062776-01
Application #
9722022
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Wise, Bradley C
Project Start
2019-06-01
Project End
2021-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158