Biology subjects

Scanlan, T. S.

Publications and source records attributed to Scanlan, T. S..

5 recordsLinked to original sources

bioRxiv2026

The TREM2 targeting small molecule Sob-AM2 improves cognition independent of Aβ plaque alteration in 5xFAD mice

BackgroundInflammation is an early event that substantially influences Alzheimers disease (AD) pathogenesis, making it a compelling target for therapeutic intervention. Sob-AM2 is a brain-penetrating thyromimetic drug capable of inducing the expression of microglial cell surface receptor TREM2, which mediates the switch from pro-inflammatory to a more restorative microglial state. ObjectiveEvaluate the effects of Sob-AM2 on cognition, AD pathology and microglial activity in the 5xFAD mouse model of amyloid-beta (A{beta}) accumulation. MethodsSeven-month-old 5xFAD mice and their wild-type littermates were administered Sob-AM2 subcutaneously three times per week for 12 weeks. In the last two weeks of treatment mice underwent behavioral tests to assess cognition and monitor for off-target mobility effects. At the end of treatment, brain tissue was harvested for gene and protein expression analyses. ResultsSob-AM2 treatment increased TREM2 expression in the brains of 5xFAD mice. This was accompanied by an improvement in both spatial and associative memory as well as an increase in the expression of synaptic genes synaptophysin and PSD-95. No significant changes were detected in A{beta} plaque burden or the expression of microglial activation marker Iba1 in Sob-AM2 treated animals, however, the expression of the phagocytic marker CD68 was significantly increased in the hippocampus, but not the cortex, in Sob-AM2 treated 5xFAD mice. ConclusionThese results suggest that the cognitive-enhancing effects of Sob-AM2 are not the result of reduced overall plaque burden. Future work is needed to further investigate the neuroprotective mechanism of Sob-AM2 and how it may be affecting microglial phenotypes.

neuroscience↗

bioRxiv2026

Elunetirom, a brain-targeted TRβ prodrug, promotes neuronal plasticity and mitochondrial biogenesis-related signaling in primary neuronal cultures

Major depressive disorder and bipolar depression are disabling illnesses associated with impaired neuroplasticity, mitochondrial dysfunction, and altered cellular bioenergetics. Available pharmacotherapies often have delayed onset, incomplete efficacy, and limited effects on underlying plasticity and energetic systems. Non-selective thyroid hormone therapies provide evidence that enhancing central thyroid hormone signaling may improve depressive symptoms, but systemic cardiovascular, skeletal, and metabolic effects limit their broader use. Rapid-acting treatments such as esketamine and psychedelics further support neuroplasticity as a therapeutic strategy, although psychotomimetic, hallucinogenic, and implementation burdens may constrain widespread use. Elunetirom is a brain-targeted, fatty acid amide hydrolase-sensitive prodrug of LL-340001, a potent thyroid hormone receptor activator as demonstrated in transfected cell-line and brain-slice target-engagement assays. We evaluated elunetirom and LL-340001 in primary cortical and mature hippocampal neuronal cultures. LL-340001 increased MAP-2-positive neuron number, neurite length, branching, and neurite extremities in immature cortical neurons. In mature hippocampal neurons, elunetirom rapidly increased neurite network and synapse number within 24 hours, with effects persisting through 72 hours, while LL-340001 preserved synapse number following amyloid-{beta}1-42 challenge. LL-340001 also increased nuclear PGC-1 and NRF2, the number of functional mitochondria measured by MitoTracker, and ATP content. Pharmacologic inhibition indicated that the LL-340001-induced increase in cortical MAP-2-positive neuron number was sensitive to TrkB inhibition but not 5-HT2A antagonism. Together, these findings indicate that elunetirom and LL- 340001 engage complementary neuroplasticity and mitochondrial biogenesis-related programs in neuronal systems and support further investigation of brain-targeted thyromimetic signaling as a mechanistically differentiated approach for major depressive disorder and bipolar depression.

neuroscience↗

bioRxiv2021

TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. We report here that TREM2 is a thyroid hormone regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone. Both endogenous thyroid hormone and sobetirome, a synthetic thyroid hormone agonist drug, suppress pro-inflammatory cytokine production from myeloid cells including macrophages that have been treated with the SARS-CoV-2 spike protein which produces a strong, pro-inflammatory phenotype. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia, a phenotype consistent with activation of the TREM2 pathway. The thyroid hormone antagonist NH-3 blocks the anti-inflammatory effects of thyroid hormone agonists and suppresses microglia phagocytosis. Finally, in a murine experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model, treatment with Sob-AM2, a CNS-penetrating sobetirome prodrug, results in increased Trem2 expression in disease lesion resident myeloid cells which correlates with therapeutic benefit in the EAE clinical score and reduced damage to myelin. Our findings represent the first report of endocrine regulation of TREM2 and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small molecule therapeutic agents.

immunology↗

bioRxiv2020

Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE

We have previously demonstrated that thyromimetics stimulate oligodendrocyte precursor cell differentiation and promote remyelination in murine demyelination models. We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE). Compared to controls, EAE mice receiving triiodothyronine (T3, 0.4mg/kg), Sob (5mg/kg) or Sob-AM2 (5mg/kg) had reduced clinical disease and, within the spinal cord, less tissue damage, more normally myelinated axons, fewer degenerating axons and more oligodendrocytes. T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis. HighlightsO_LIThyroid hormone, the thyromimetic Sob and its CNS penetrating prodrug, Sob-AM2, reduce disease severity, reduce myelin and axonal degeneration and protect oligodendrocytes in EAE. C_LIO_LIThe benefits of Sob and Sob-AM2 may be via direct protective effects on oligodendrocytes and reduction in activity of microglia/macrophages. C_LI

neuroscience↗

bioRxiv2019

Pharmacological complementation remedies an inborn error of lipid metabolism

X-linked adrenoleukodystrophy (X-ALD) is a rare, genetic disease in which increased very long chain fatty acids (VLCFAs) in the central nervous system (CNS) cause demyelination and axonal degeneration, leading to severe neurological deficits. Sobetirome, a potent thyroid hormone agonist, has been shown to lower VLCFA levels in the periphery and CNS. In this study, two pharmacological strategies for enhancing the effects of thyromimetics were tested in Abcd1 KO mice, a murine model that has the same inborn error in metabolism as X-ALD patients. First, a sobetirome prodrug (Sob-AM2) with increased CNS penetration lowered CNS VLCFAs more potently than sobetirome, and was better tolerated with lower peripheral exposure, but was unable to unable to break the efficacy threshold of CNS VLCFA lowering in Abcd1 KO mice. Second, co-administration of thyroid hormone with sobetirome enhanced VLCFA lowering in the periphery compared to sobetirome alone but did not produce greater lowering in the CNS. These data suggest that the extent of CNS VLCFA lowering in Abcd1 KO mice is limited by a mechanistic threshold related to slow turnover kinetics, potentially related to the lack of frank X-ALD disease in this model. However, Sob-AM2 has improved potency at correcting the lipid abnormality associated with X-ALD in the CNS with better tolerance than the parent drug sobetirome.

pharmacology and toxicology↗