Targeting microglial HK2 to treat traumatic brain injury and prevent progression to alzheimer's-like dementia

Overview

This research program addresses the critical unmet need of preventing the long-term neurological consequences of traumatic brain injury (TBI), including its progression to Alzheimer's disease and related dementias (AD/ADRD). The core innovation is the targeting of hexokinase 2 (HK2), a key glycolytic enzyme in microglia, the resident immune cells of the brain. Persistent microglial activation is a known driver of chronic inflammation after TBI, and this work demonstrates that HK2 is a central regulator of the metabolic-inflammatory cycle that perpetuates secondary brain injury and accelerates amyloid pathology.

The therapeutic strategy involves partial antagonism or genetic reduction of HK2 to temper microglial activation, reduce amyloid burden, and improve cognitive performance. This approach has been validated in both wild-type and 5xFAD amyloid mouse models subjected to mild TBI, showing reductions in toxic amyloid-beta oligomers, decreased inflammatory cytokines, and recovery from hippocampal atrophy.

Technical specifications

Key scientific findings:

• HK2 expression is significantly upregulated from 3 to 30 days post-injury in the ipsilateral cortex of mice subjected to controlled cortical impact (CCI)
• Immunohistochemistry confirms that activated microglia near the injury site are the primary source of increased HK2
• Pharmacological inhibition of HK2 with lonidamine (LND) reduces microglial activation markers and inflammatory cytokine levels
• HK2 haploinsufficiency or pharmacological inhibition reduces TBI-induced accumulation of toxic 14-mer amyloid-beta oligomers in 5xFAD mice
• Treatment with HK2 inhibitors restores hippocampal integrity and motor lateralization deficits in the Y-maze test

Planned validation activities:

• Spatial transcriptomic profiling of microglia following genetic or pharmacological HK2 antagonism post-TBI
• Evaluation of therapeutic window by administering HK2 inhibitors at different stages post-injury
• Assessment of AD pathology acceleration in 5xFAD mice with microglia-specific HK2 deletion, including cognition, amyloid species, tau phosphorylation, and plaque microenvironment analysis

Technology readiness level

The program is currently at Technology Readiness Level 3 (TRL 3), with proof-of-concept demonstrated in relevant animal models. Key validations have been completed in wild-type and 5xFAD mouse models of TBI, confirming the mechanistic role of HK2 in microglial dysregulation and its therapeutic potential. Next steps include expanded preclinical validation, dose-response studies, and optimization of therapeutic timing to advance toward IND-enabling studies and potential clinical translation.