Evaluating a novel, orally-active TREM2-targeting drug in AD

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Project Summary Neuroinflammation, characterized by microglial activation and increased pro-inflammatory cytokine production, is evident early in Alzheimer's disease (AD) and appears to play an important role in disease progression. Signaling through TREM2 (Triggering receptor expressed on myeloid cells 2) mediates this inflammatory response through effects on microglial activation. TREM2 has also been recognized as a risk factor for AD with missense mutations in the gene being associated with increased risk of AD and elevated levels of TREM2 in the cerebrospinal fluid correlating with decreased disease severity. Excitingly, TREM2 was recently shown by members of our study team to be a druggable target by the newly designed, orally available agent, Sob-AM2. While Sob-AM2 has shown to be neuroprotective in other neurodegenerative disease models where neuroinflammation and cognitive impairment are also evident, it has not yet been developed for use in AD. The studies proposed here will begin to fill in these existing gaps in the preclinical testing of Sob- AM2. In Aim 1 we will optimize the concentration of oral Sob-AM2 needed to elicit maximum increases in TREM2 expression in the brain without evoking toxicity. Aims 2 and 3 will utilize the identified dose, determine the optimal timing of treatment initiation and assess efficacy in AD mouse models. Aim 2 will use the 5xFAD model of beta-amyloid accumulation while Aim 3 will use the PS19 model of tauopathy to investigate the effects of an early versus late start of oral Sob-AM2 treatment on the downstream effects of TREM2 activation on AD pathology as well as neurodegeneration, cognition and neuroinflammation. We will also monitor the downstream targets of thyroid hormone signaling to identify non-TREM2 related effects of Sob-AM2 as well as to ensure that there is no evidence of aberrant signaling and that peripheral off-target effects are not seen. This work will address critical questions surrounding dosage and treatment duration of the first orally active, small molecule drug to target TREM2. Given the lack of disease modifying AD therapies, Sob-AM2 is a very promising candidate drug to develop for use in AD and completion of these essential preclinical studies described in this project will greatly accelerate its eventual clinical translation.