Interneuron dysfunction and the emergence of tau pathology in early Alzheimer’s disease - 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.
