Li, Yonghe

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.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

AbstractBackgroundThe accumulation of the amyloid‐β (Aβ) aggregates in the brain is a key pathological event in the development of Alzheimer’s disease (AD). The α‐secretase ADAM10 is responsible for cleavage of the amyloid precursor protein (APP) through a non‐amyloidogenic pathway, thereby preventing the generation of pathogenic Aβ in the brain. Secreted frizzled related protein‐1 (sFRP1), an endogenous antagonist of Wnt signaling, has recently been identified as a key negative modulator of ADAM10. Importantly, proteomic studies reveal that unregulated sFRP1 is one of the top Aβ‐correlated proteins in the human AD brains.MethodsWe determined the therapeutic potential of specific sFRP1 WAY316606 in the N2a/APP695swe cells and patient‐specific iPSC‐derived cerebral organoids.ResultsWe herein demonstrated that treatment of sFRP1 inhibitor WAY316606 resulted in augmentation of ADAM10 activity, upregulation of soluble APP‐α (sAPPα) production, and inhibition of Aβ generation in the N2a/APP695swe cells. Moreover, WAY316606 significantly enhanced ADAM10 activity, decreased Aβ production and inhibited tau phosphorylation in human AD patient‐specific iPSC‐derived cerebral organoids.ConclusionOur findings indicate that sFRP1 is a promising therapeutic target for AD.

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.

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of age‐related dementia characterized by the presence of amyloid‐β (Aβ) and tau pathologies leading to neurodegeneration and cognitive impairment. Wnt/β‐catenin signaling modulates multiple pathophysiological processes including synaptic plasticity, neuronal survival, neuroinflammation, Aβ production and tau phosphorylation, but this signaling pathway is greatly inhibited in the AD brain. Notably, two SNPs and an alternative splice variant of Wnt co‐receptor LRP6, which result in down‐regulation of Wnt/β‐catenin signaling, are associated with increased risk of developing AD. In addition, apoE4, the strongest risk factor of late‐onset AD, interacts with and decreases cell surface abundance of LRP6 in astrocytes. Studies from our laboratory have demonstrated that the level of LRP6 is significantly downregulated in human AD brains, and that deficiency in LRP6‐mediated Wnt/β‐catenin signaling leads to synaptic abnormalities and amyloid pathology in amyloid model mice. Therefore, LRP6 is an attractive therapeutic target for restoring Wnt/β‐catenin signaling in the AD brain.MethodIn our previous studies, we have discovered niclosamide, an FDA‐approved anthelminthic drug, inhibits Wnt/β‐catenin signaling via promoting LRP6 degradation. Herein, we demonstrated that CI‐994, an analog of niclosamide, exhibits opposite effects on LRP6 level and Wnt/β‐catenin signaling. Following structural optimization, we have generated a series of novel potent Wnt modulators.ResultThe leading compound W2A‐16 displays a good pharmacokinetic profile with high oral bioavailability and brain penetration. Importantly, W2A‐16 significantly activates Wnt/β‐catenin signaling and inhibits tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids. Moreover, W2A‐16 attenuates amyloid pathology and gliosis and improves cognitive function in 5xFAD amyloid model mice. Further, W2A‐16 suppresses tau phosphorylation and neuroinflammation, attenuates body weight loss, and improves the survival of PS19 tauopathy mice.ConclusionTogether, these findings demonstrate that W2A‐16 is a strong drug candidate for AD therapy.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.

AbstractIntroductionCerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood‐brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases.MethodsWe performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin‐5 (CLDN5) and occludin (OCLN), and major AD‐related molecules (amyloid beta [Aβ40], Aβ42, tau, p‐tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.ResultsHigher levels of soluble tau, insoluble p‐tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.DiscussionRefining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.