Harvard Catalyst Profiles

Project Summary There are no efficacious therapies available to halt or reverse AD progression, which is attributed to, in part, the lack of translational cross-species biomarkers suitable in both preclinical disease models and humans to facilitate drug discovery and development process. Therefore, development of translatable imaging biomarkers for non-invasive assessment of disease progression and therapeutic efficacy hold promises to fill the gap of this urgent and unmet clinical need. Growing evidence indicates altered microglia and neuroimmune function disruption occurs early in the AD pathophysiology. We have also seen that early intervention against neuroinflammation could substantially impact the incidence and progression of AD. Herein we propose the use of a novel imaging strategy for monitoring innate immune function, neuroinflammation, and microglia-modulating treatment response in AD therapy. Our strategy involves the use of a specific positron emission tomography (PET) tracer [18F]JNJ-739 targeting purinergic P2X7 receptor (P2X7R). Increased P2X7R expression has been found in microglial cells surrounding amyloid plaques both in AD patients and different AD mouse models, which parallels with AD progression. [18F]JNJ-739 is the only validated P2X7R PET tracer that showed high permeability and specific binding in the brain of nonhuman primates and has recently translated to human use. The ligand possesses excellent binding affinity (IC50 1.0 nM) and high selectivity (>100 fold) towards any other major CNS targets. The PI and his team have evaluated brain kinetic and specific binding of [18F]JNJ-739 in neuroinflammation mouse models. Our preliminary studies have shown that [18F]JNJ-739-PET can detect and monitor neuroinflammation in LPS-induced neuroinflammation mouse models, which was well-correlated with our immunohistological findings. To date, there is no direct non-invasive in vivo measurement of the distribution and expression of P2X7R in various AD stages, representing a substantial knowledge gap and opportunity to study microglia activation and innate immune function by [18F]JNJ-739-PET. Our hypothesis entails that increased P2X7R brain binding, determined by [18F]JNJ-739-PET, is correlated with AD symptom severity, increased neuroinflammation, activated microglia and severe innate immune disruption, as well as high A?/tau production. Therefore, as our specific objectives, utilizing non-invasive [18F]JNJ-739-PET, we propose to directly monitor P2X7R changes in the brain as an index of neuroinflammation and altered microglia in AD, and determine target engagement. Following this, our long-term goal is to assess the utility of [18F]JNJ-739-PET as a translational biomarker to provide new information of AD pathophysiology and to evaluate treatment response in clinical trials of novel AD drugs.

R21AG074218

LIANG, STEVEN HUAN

2021-09-01

2023-06-30