Cell therapy for Alzheimer's disease

About This Grant

Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is one of the leading causes of dementia. In addition to memory deficits, Alzheimer’s patients exhibit sleep impairments. Aberrant neuronal circuit activity contributes to the disease etiology and its progression. Anomalies in sleep-dependent brain rhythms, specifically slow oscillations important for consolidation of memories during NREM sleep, have been reported in Alzheimer’s patients. Multiple lines of evidence suggest that disruptions in slow oscillations facilitate Alzheimer’s progression and might contribute to dementia. Thus, aberrant slow wave activity is not simply symptomatic but can be targeted with therapies. Therefore, it is necessary to develop therapeutic strategies targeting restoration of circuit function, such as slow wave activity, to rescue cognitive impairments associated with sleep-dependent memory dysfunction. Stem cell-based therapies are being developed for a number of neurological disorders and could be applicable to Alzheimer’s disease. Alzheimer’s disease is characterized by circuit hyperexcitation at early prodromal stages due to deficits in inhibition, thus disrupting slow brain rhythms, including slow oscillations. Thus, restoration of inhibitory tone through transplantation of inhibitory interneuron progenitors might restore circuit function and slow Alzheimer’s progression. We show that isolation of embryonic mouse MGE-derived interneuron progenitors and their transplantation into an animal model of amyloidosis restores slow wave activity in young mice. We will test the degree to which cell therapy slows neuropathophysiology and rescues sleep as well as memory impairments. Furthermore, to increase translational impact of this work, we will transplant human iPSC-derived interneuron progenitors and determine their role on circuit function and Alzheimer’s progression in a mouse model of amyloidosis. We will implement leading-edge methodology including imaging with voltage-sensors and high-resolution multiphoton microscopy to monitor circuit function as well as optogenetics to control neuronal activity with high temporal precision. Thus, as a result of this work we will evaluate the efficacy of stem cell therapy using mouse and human progenitors for the treatment of Alzheimer’s disease in a mouse model of amyloidosis. This work will provide strong bases for translating cell therapy as a cure to slow AD progression in patients as part of a novel therapeutic approach.