Evaluation of Chorionic Gonadotropin as a Treatment for Sepsis-induced Neuroinflammation and Cognitive Dysfunction in the Aged Brain

PROJECT SUMMARY
Seventy percent of sepsis patients show some degree of acute diffuse neurological impairment. Importantly
about half show chronic neurocognitive impairments, ten percent of which are noted to be severe. In older
individuals the incidence of sepsis is significantly higher as is the risk of long-term severe cognitive impairment.
Given the rapidly increasing numbers of aged individuals and the significant economic and functional burden
that this poses to the individual and the families of these patients, identifying neuroprotective therapies to prevent
long-term changes in the brains of sepsis patients is of high significance to the field. This is particularly important
since increasing data suggests a strong link between sepsis and later development of dementia, an aspect that
is recapitulated in rodent AD models, were sepsis increases pathology associated with this disease. However,
despite the high incidence and clinical relevance of neurological disturbances during and after sepsis, the
pathological mechanisms underlying both acute and chronic neurological dysfunction are not fully understood.
To date, there are no effective therapies to treat or mitigate these long-term sequalae.
A key emerging mechanism linking sepsis to cognitive impairment involves immune cell infiltration into the
CNS secondary to blood brain barrier dysfunction during the acute phase of the infection. To this end, we have
identified that the luteinizing hormone receptor agonist, hCG, which we have previously shown to protect
cognition in aging menopausal and AD mouse models, has powerful anti-inflammatory effects within the brain.
These are in line with the expression of this receptor by microglia and excitatory neurons in the brain but also
parallel the established role for this hormone in the periphery where, during pregnancy, it is a major regulator of
key immune cells (i.e. neutrophils and monocytes) that are known to infiltrate and cause cognitive dysfunction in
sepsis models. Therefore, we seek to address whether 1) hCG will prevent long-term cognitive dysfunction
associated with sepsis in aged mice and 2) whether these benefits are associated with the regulation of
peripheral cell infiltration and/or centrally mediated pro-inflammatory mechanisms. Notably, given the
involvement of this inflammatory mechanism in other neurological disorders (TBI, neurogenerative disorders,
stroke) the mechanistic evaluation of LHCGR agonists can be readily generalizable to other CNS conditions that
impact the aged brain.

Grant Number: 1R21AG087039-01
NIH Institute/Center: NIH
Principal Investigator: Gemma Casadesus