Joungil Choi

A variety of evidence now supports two interrelated hypotheses concerning Alzheimer’s disease (AD) neurofibrillary pathology (NFT), its prevention and treatment. The first hypothesis: the receptor type protein tyrosine phosphatase D (PTPRD) plays a key role in AD NFT pathogenesis by modulating activities of neuronal glycogen synthase kinase 3s (GSK3s) in hyperphosphorylating tau. The second hypothesis: positive allosteric modulation of PTPRD’s downregulation of GSK3s by flavonols and improved flavonol analogs provides a novel path to prevention and treatment of AD. We review the convergence of evidence from human, mouse, in vitro and in silico studies that enhances the likely translational relevance of these hypotheses.

Diabetes increases the risk of cognitive impairment and Alzheimer’s disease, but the mechanisms linking metabolic stress to hippocampal neurodegeneration remain unclear. We investigated whether disruption of PINK1-AMPK signaling contributes to Diabetes Induced Cognitive Impairment (DCI) and whether activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) prevents critical metabolic, cognitive, and neuropathology processes. Hippocampal tissue from diabetic and non-diabetic human brains was analyzed for PINK1-AMPK pathway proteins and tau phosphorylation. In parallel, PINK1 wild-type and PINK1 knockout mice were fed a control diet or high-fat diet, with or without AICAR, and assessed using biochemical, mitochondrial, magnetic resonance spectroscopy, lipid, neuropathological, and behavioral measures. Diabetic human hippocampus showed reduced PINK1, phospho-AMPK, and PGC-1α levels with increased phosphorylated tau. High-fat diet feeding reproduced these changes in mice and produced greater oxidative stress, impaired mitochondrial turnover, lipid droplet accumulation, reduced neuronal metabolic markers, and increased amyloid-beta and phosphorylated tau in PINK1 knockout mice. AICAR increased AMPK phosphorylation, promoted mitochondrial mitophagy, reduced oxidative stress, and lipid accumulation. Furthermore, upregulation of AMPK by AICAR lowered amyloid-beta and phosphorylated tau levels, prevented loss of hippocampal CA1 neurons, and reduced deficits in spatial and object recognition memory. These findings show impaired PINK1-AMPK signaling is critical in biological, cognitive, and pathological processes associated with DCI. AICAR/AMPK activation is a potential therapeutic strategy for DCI.

Breast cancer gene 1 (BRCA1) is a tumor suppressor gene essential for DNA repair, and its mutations are linked to aggressive breast cancers with poor prognosis. While poly (ADP-ribose) polymerase (PARP) inhibitors benefit some patients with BRCA1-mutant, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, issues such as limited efficacy and drug resistance persist. This is especially critical for triple-negative breast cancer (TNBC), which lacks targeted therapies. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as abemaciclib—FDA-approved for estrogen receptor (ER)-positive/HER2-negative breast cancer—are emerging as potential treatments for TNBC. We evaluated abemaciclib in BRCA1-mutant TNBC cell lines (SUM149, HCC1937, and MDA-MB-436) and found them to be sensitive to the drug. However, treatment induced cellular senescence and Interleukin-6 (IL-6) secretion, which may promote drug resistance. To address this, we inhibited IL-6 signaling using bazedoxifene or glycoprotein 130 (GP130) siRNA, and both of which enhanced abemaciclib sensitivity. Combination treatment with bazedoxifene and abemaciclib synergistically inhibited cell migration and invasion, and induced apoptosis. In a mammary fat pad TNBC tumor model, the combination treatment significantly suppressed SUM149 tumor growth more than either agent alone. These findings support co-targeting IL-6 and CDK4/6 as a novel therapeutic strategy for BRCA1-mutant TNBC.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in both Type 1 (T1D) and Type 2 (T2D). While there are no specific medications to prevent or treat DPN, certain strategies can help halt its progression. In T1D, maintaining tight glycemic control through insulin therapy can effectively prevent or delay the onset of DPN. However, in T2D, overall glucose control may only have a moderate impact on DPN, although exercise is clearly beneficial. Unfortunately, optimal exercise may not be feasible for many patients with DPN because of neuropathic foot pain and poor balance. Exercise has several favorable effects on health parameters, including body weight, glycemic control, lipid profile, and blood pressure. We investigated the impact of an exercise mimetic, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on DPN. AICAR treatment prevented or reversed experimental DPN in mouse models of both T2D and T1D. AICAR in high-fat diet (HFD-fed) mice increased the phosphorylation of AMPK in DRG neuronal extracts, and the ratio of phosphorylated AMPK to total AMPK increased by 3-fold (HFD vs. HFD+AICAR; p < 0.001). Phospho AMP increased the levels of dynamin-related protein 1 (DRP1, a mitochondrial fission marker), increased phosphorylated autophagy activating kinase 1 (ULK1) at Serine-555, and increased microtubule-associated protein light chain 3-II (LC3-II, a marker for autophagosome assembly) by 2-fold. Mitochondria isolated from DRG neurons of HFD-fed had a decrease in ADP-stimulated state 3 respiration (120 ± 20 nmol O₂/min in HFD vs. 220 ± 20 nmol O₂/min in control diet (CD); p < 0.001. Mitochondria isolated from HFD+AICAR-treated mice had increased state 3 respiration (240 ± 30 nmol O₂/min in HFD+AICAR). However, AICAR’s protection in DPN in T2D mice was also mediated by its effects on insulin sensitivity, glucose metabolism, and lipid metabolism. Drugs that enhance AMPK phosphorylation may be beneficial in the treatment of DPN.