Bri2 BRICHOS chaperone rescues impaired fast-spiking interneuron behavior and neuronal network dynamics in an AD mouse model in vitro

Synchronized and properly balanced electrical activity of neurons is the basis for the brain's ability to process information, to learn, and to remember. In Alzheimer's disease (AD), which causes cognitive decline in patients, this synchronization and balance is disturbed by the accumulation of neuropathological biomarkers such as amyloid-beta peptide (A842). Failure of A842 clearance mechanisms as well as desynchronization of crucial neuronal classes such as fast-spiking interneurons (FSN) are root causes for the disruption of the cognitionrelevant gamma brain rhythm (30-80 Hz) and consequent cognitive impairment observed in AD. Here we show that recombinant BRICHOS molecular chaperone domains from ProSP-C or Bri2, which interfere with A842 aggregation, can rescue the gamma rhythm. We demonstrate that A842 progressively decreases gamma oscillation power and rhythmicity, disrupts the inhibition/excitation balance in pyramidal cells, and desynchronizes FSN firing during gamma oscillations in the hippocampal CA3 network of mice. Application of the more efficacious Bri2 BRICHOS chaperone rescued the cellular and neuronal network performance from all ongoing A842induced functional impairments. Collectively, our findings offer critical missing data to explain the importance of FSN for normal network function and underscore the therapeutic potential of Bri2 BRICHOS to rescue the disruption of cognition-relevant brain rhythms in AD.

Automated summary

The synchronized and balanced electrical activity of neurons is crucial for the brain to process information, learn, and remember. In Alzheimer's disease, cognitive decline is caused by the disruption of this synchronization and balance due to the accumulation of neuropathological biomarkers such as A842, which impairs crucial neuronal classes and cognitive brain rhythms. The use of recombinant BRICHOS molecular chaperone domains shows promise in rescuing the disruption of cognition-relevant brain rhythms in AD.