Ksenia Kastanenka

About Ksenia Kastanenka
Ksenia Kastanenka is an Assistant Professor at Massachusetts General Hospital and Harvard Medical School, where she runs a research laboratory with emphasis on neurodegeneration and Alzheimer’s disease. Her laboratory focuses on circuitry disruption during the disease progression and mechanisms of action of Alzheimer’s therapeutics.

Ksenia has over 15 years of experience studying neuronal circuits. During her PhD work at Case Western Reserve University in Cleveland, OH, she used state of the art laboratory techniques, including optogenetics, to study the assembly of spinal circuits during development. 10 years ago, Dr. Kastanenka extended her expertise into the field of Alzheimer’s disease. At Massachusetts General Hospital and Harvard Medical School in Boston, MA, she has developed a line of work applying optogenetics and multiphoton microscopy to dissect the role sleep-dependent brain rhythms play in the etiology and progression of Alzheimer’s disease.

Watch Ksenia Kastanenka’s NPC Symposium talk below.

Interested in learning more? Check out the Q&A session:

Applying Optogenetics to Studies of Alzheimer’s Disease.
Slow oscillations are important for consolidation of memory during sleep, and Alzheimer’s disease (AD) patients experience memory disturbances. Thus, we examined slow oscillations in an animal model of AD (APP mice). The power of slow oscillations at 0.6Hz was decreased starting at 3 months of age. Soluble amyloid-beta was sufficient to disrupt the slow waves. Cortical GABA levels were low in APP mice and application of exogenous GABA restored the slow oscillations, indicating that aberrant excitatory activity within the cortical circuit was responsible for slow oscillation dysfunction. Next, we sought to manipulate slow waves in APP mice with optogenetics. Driving slow oscillations at normal frequency with light activation of channelrhodopsin-2 (ChR2) expressed in excitatory cortical neurons restored slow wave power by synchronizing neuronal activity. Using multiphoton microscopy, we performed longitudinal imaging of senile plaques and monitored intracellular calcium.

Cytosolic calcium is a surrogate marker of neuronal activity and is normally tightly regulated. We had previously demonstrated that resting calcium levels were elevated in a subset of neurons in APP transgenics, and hypothesized that an effective treatment would restore calcium to control levels. Driving slow oscillation activity with optogenetics halted amyloid plaque deposition and prevented calcium overload associated with this pathology. On the other hand, driving slow oscillation activity at twice the normal frequency (1.2Hz) resulted in increased amyloid production, increased amyloid plaque deposition, disruptions in neuronal calcium homeostasis, and loss of synaptic spines. Therefore, while restoration of physiological circuit dynamics is sufficient to abrogate the progression of Alzheimer’s disease pathology and should be considered an avenue for clinical treatment of patients with sleep disorders, pathophysiological stimulation of neuronal circuits leads to activity dependent acceleration of amyloid production, aggregation and downstream neuronal dysfunction.

The Kastanenka Lab
Learn more about the Kastenenka Lab here.