Jeevaratnam, Suren

Abstract Alzheimer’s disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.

Abstract Background Alzheimer’s disease (AD) is a multifactorial disease often with mixed pathologies. As such, drugs targeting multiple pathological processes simultaneously could have synergistic therapeutic effects. The histone acetylation homeostasis is greatly impaired in AD, and histone deacetylase (HDAC) inhibitors have been known to alleviate AD‐relevant pathologies in various animal models. In addition, Wnt/β‐catenin signaling is compromised in AD, and restoring Wnt/β‐catenin signaling is an attractive therapeutic strategy for AD treatment. CI‐994 is a class I HDAC inhibitor containing N‐(2‐aminophenyl)‐benzamide. Our recent studies indicate that CI‐994 is also an activator of Wnt/β‐catenin signaling by stabilizing Wnt co‐receptor LRP6. Method We use CI‐994 as a scaffold to develop novel potent dual modulators for class I HDAC inhibition and Wnt/β‐catenin signaling activation, and then determine the therapeutic potential of the lead compound W2A‐28 in AD patient‐specific iPSC‐derived cerebral organoids. Result W2A‐28 inhibits class I HDAC1, 2 and 3 activities with IC 50 values of 512 nM, 675 nM and 217 nM, respectively, with no inhibitory activities on other HDACs and Sirtuin family members. Furthermore, W2A‐28 greatly increases Wnt reporter activity with an EC 50 value of 1.61 µM in Wnt‐3A‐expressing HEK293 cells. As expected, activation of Wnt/β‐catenin signaling by W2A‐28 is associated with elevated Wnt co‐receptor LRP6 protein level by reducing LRP6 degradation. Importantly, W2A‐28 displays excellent aqueous solubility and microsomal stability. Further, W2A‐28 shows high permeability with no active efflux in MDR1‐MDCKII permeability assays and is not a P‐gp substrate. Finally, W2A‐28 significantly reduces Aβ40 and Aβ42 levels and suppresses tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids carrying APOE4. Conclusion Our studies suggest that W2A‐28 is a potential drug candidate for the treatment of AD.

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of age‐related dementia, and the presence of amyloid‐β (Aβ) plaques and tau‐containing neurofibrillary tangles is associated with the neurodegeneration and cognitive impairment in this incurable disease. Growing evidence shows that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in AD, and HDACs have been highlighted as a novel class of anti‐Alzheimer targets. Moreover, restoring Wnt/β‐catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy for AD. CI‐994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI‐994 can cross the blood‐brain barrier and is a cognitive enhancer.MethodWe evaluated the therapeutic potential of CI‐994 in human patient‐specific iPSC‐derived neurons and cerebral organoids with APOE ε4/ε4 genotype or carrying MAPT p.P301L mutation.ResultWe found that CI‐994 is not only a potent class I HDAC inhibitor but also a novel modulator of Wnt/β‐catenin signaling, and that activation of Wnt/β‐catenin signaling by CI‐994 is associated with elevated Wnt co‐receptor LRP6 protein level. Moreover, CI‐994 increased synaptic protein levels, enhanced spontaneous synaptic firing and network formation, and decreased tau phosphorylation in iPSC‐derived neurons. Finally, CI‐994 significantly increased histone acetylation, activated Wnt/β‐catenin signaling, and decreased Aβ production and tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids.ConclusionOur findings indicate that CI‐994 is a novel potential therapeutic candidate for AD.

Abstract Hydroxychloroquine (HCQ) induced cardiotoxicity is a rare diagnosis and is often associated with chronic use of the medication. It has been shown that chronic HCQ use is associated with a drug-induced cardiomyopathy mainly driven by acquired lysosomal storage defects leading to hypertrophy and conduction abnormalities. As the only proven treatment is the discontinuation of the offending agent, prompt recognition is required to avoid further exposure to the drug and potential progression of disease. History, physical examination and advanced imaging modalities are useful diagnostic tools, but more invasive testing with an endomyocardial biopsy is required for definitive diagnosis. We present a descriptive case series of ten patients that were diagnosed with biopsy proven HCQ cardiotoxicity.

The prevalence of Alzheimer’s disease is greater in women, but the underlying mechanisms remain to be elucidated. We herein demonstrated that α-secretase ADAM10 was downregulated and ADAM10 inhibitor sFRP1 was upregulated in 5xFAD mice. While there were no sex effects on ADAM10 protein and sFRP1 mRNA levels, female 5xFAD and age-matched non-transgenic mice exhibited higher levels of sFRP1 protein than corresponding male mice. Importantly, female 5xFAD mice accumulated more Aβ than males, and sFRP1 protein levels were positively associated with Aβ42 levels in 5xFAD mice. Our study suggests that sFRP1 is associated with amyloid pathology in a sex-dependent manner.

Introduction Poor‐grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with high mortality. Overall, 20–30% of aSAH are described as poor grade. Despite recent advances in management strategies, prognosis of poor‐grade aSAH remains dismal. As such, we review the most current literature regarding management strategies that can be used to decrease the risk of the four most common causes of secondary brain injury: 1) aneurysm re‐rupture, 2) hydrocephalus, 3) cerebral salt wasting, and 4) delayed cerebral ischemia/vasospasm. Methods We present a 46‐year‐old female patient with poor‐grade aSAH after a loss of consciousness following thunderclap headache. Examination showed a dilated left pupil and Glasgow Coma Scale (GCS) of 4. Imaging revealed a ruptured anterior communicating artery aneurysm, and she was subsequently taken to the neuro‐interventional radiology suite for EVD placement. On POD 7 Transcranial Doppler (TCD) suggested moderate vasospam of left MCA. Two successful balloon angioplasties of the basilar, ACA‐A1, and MCA‐M1 were successfully performed on separate consecutive days. By POD 10, intermittent severe ICP spikes required targeted temperature management (TTM) with hypothermia. On POD 24, her ICP normalized, she was no longer comatose, and her EVD was clamped and removed. She was rapidly weaned off ventilator and transitioned to rehabilitation. 3‐months postoperatively, Modified Rankin Scale score was 0. Results Based upon the result of our literature review, we propose maintaining blood pressure below 160 mmHg prior to intervention, after which it can be increased to 160–240 mmHg to prevent vasospasm. Transcranial Doppler is essential to detect vasospasm as the aSAH symptoms subtle; once identified, vasospasm can be successfully treated with balloon angioplasty. Finally, targeted temperature management, mannitol, hypertonic saline, and neuromuscular paralysis are essential for postoperative management of ICP levels. Conclusions The multimodal approach should be considered when managing poor grade aSAH. Further research in aSAH management would benefit the patients who present with poor prognosis, thereby improving patient care and leading to a standard, effective approach for aSAH management.