We utilize the basic concepts of control theory and an integrative approach which spans brain-state, neural circuit, synaptic and molecular levels to boost cognitive resilience to AD pathology1,2.

UNMET NEED
There is no efficient, disease-modifying therapy at present for Alzheimer’s disease (AD). Even the most successful, recently FDA approved anti-amyloid drug lecanemab shows a great efficiency in removal of amyloid burden, while only minor improvements of cognitive functions related to dementia.

OUR SOLUTION
Instead of targeting AD triggers, we are working on drivers, leading to the transition from presymptomatic to clinical AD phase.
1. We propose to diagnose presymptomatic AD stage by detecting neuronal hyperexcitability in hippocampal networks during short anesthesia session (3).
2. We propose to prevent/restore hyperexcitability, sleep and memory disturbances by in cortico-hippocampal circuits using deep brain stimulation of the thalamic nucleus reuniens (DBS-nRE) by specific patterns of stimulation:
a. DBS-nRE to prevent/restore age-dependent synaptic plasticity, sleep and cognitive functions in AD.
b. DBS-nRE to prevent/restore post-operative cognitive decline (POCD) (4).
3. We propose to prevent/restore POCD and age-dependent cognitive decline by inhibiting mitochondrial DHODH enzyme. DHODH inhibition suppresses hyperexcitability by reducing firing rate set point.

APPLICATIONS
Diagnosis of presymptomatic AD
Prevention of memory and sleep disturbances by restoration of firing rate homeostasis.

STATUS
In progress.

INTELLECTUAL PROPERTY
PCT/IL2022/051323

REFERENCES
1 Frere, S. & Slutsky, I. Alzheimer’s Disease: From Firing Instability to Homeostasis Network Collapse. Neuron 97, 32-58, doi:10.1016/j.neuron.2017.11.028 (2018).
2 Styr, B. & Slutsky, I. Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease. Nature Neuroscience 21, 463-473, doi:10.1038/s41593-018-0080-x (2018).
3 Zarhin, D. et al. Disrupted neural correlates of anesthesia and sleep reveal early circuit dysfunctions in Alzheimer models. Cell Rep 38, 110268, doi:10.1016/j.celrep.2021.110268 (2022).
4     Shoob, S. et al. Thalamic Nucleus Reuniens Regulates Resilience to Synaptic and Cognitive Failures in Alzheimer’s Model  (under revision).