PROJECT SUMMARY
Alzheimer's disease (AD) is the most common form of dementia, causing a neurodegenerative cascade,
accompanied by two hallmarks of AD pathology: the accumulation of the amyloid-beta (Aβ) and tau proteins
into amyloid plaques and neurofibrillary tau tangles. Numerous investigational therapies have been
unsuccessful at treating cognitive impairment in AD patients. This may be because therapies were given too
late in the course of the disease, which has sparked recent investigation into alternative mechanisms emerging
prior to Aβ plaque pathology. Recent studies in AD patients and models of disease have shown circuit
hyperexcitability, or an abnormal increase in excitatory neuron firing, occurs prior to Aβ plaque pathology and
cognitive impairment. Several lines of evidence suggest that cortical circuit hyperexcitability in early AD is
related to a suppression in fast-spiking, parvalbumin-expressing interneuron (PV-INT) firing. The most common
GABAergic interneuron type, PV-INTs typically maintain the excitatory-inhibitory balance by synapsing onto
nearby excitatory principal neurons to inhibit their firing. Our preliminary data from an early-stage AD mouse
model expressing the human amyloid precursor protein (hAPP) indicates that PV-INTs in the lateral entorhinal
cortex (LEC) are particularly vulnerable, showing reduced firing which results in overall network
hyperexcitability in the LEC. Others have shown that circuit overexcitation may promote pathological tau in
excitatory neurons, however, the impact on activity at the neuronal and circuit level remain unclear.
Conversely, it is unknown whether a causal link exists between PV-INT dysfunction and pathological tau
progression. Thus, this proposal seeks to determine 1. How pathological tau effects the intrinsic
excitability of neurons, and 2. How PV-INT dysregulation alters pathological tau. In Aim 1, I predict that
pathological tau suppresses excitatory neuron firing, and thus will dampen hAPP-related hyperexcitability in the
LEC. I will use adeno-associated viruses (AAVs) in mice to express the human tau gene (hMAPT) and/or
hAPP. Neuron- and circuit-level changes in excitability will be assessed using patch-clamp electrophysiology.
In Aim 2, I predict that PV-INT hypoactivity results in circuit hyperexcitability, and thus a direct suppression of
PV-INT firing will increase pathological tau in excitatory neurons. I will use AAV-delivered chemogenetics
under direction of a PV-INT-selective enhancer to suppress firing in these neurons. Changes in pathological
tau burden will be assessed using immunohistochemistry. Together, the results of this proposal will provide
clarity on the role of pathological tau as an initial compensatory response to normalize the network balance in
early AD, and establish a cell-type-specific mechanism causally linked to pathological tau progression.