Upregulation of Wnt2b exerts neuroprotective effect by alleviating mitochondrial dysfunction in Alzheimer's disease.

AIMS: This study investigated the relationship between plasma Wnt2b levels and Alzheimer's disease (AD), and explored the effect of Wnt2b on mitochondrial dysfunction in AD. METHODS: Healthy and AD subjects, AD transgenic mice, and in vitro models were used to investigate the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT-qPCR, immunoblotting, and immunofluorescence analysis were performed to assay canonical Wnt signaling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis. RESULTS: Plasma Wnt2b levels were lower in AD patients and positively correlated with cognitive performance. Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models. Next, Wnt2b overexpression and recombinant Wnt2b were used to endogenously and exogenously upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated. CONCLUSIONS: Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and upregulation of Wnt2b can exert neuroprotective effects in AD, particularly in ameliorating mitochondrial dysfunction.

NMDA Receptor GluN2B Subunit Is Involved in Excitotoxicity Mediated by Death-Associated Protein Kinase 1 in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of neurodegenerative dementia among the elderly. Excitotoxicity has been implicated as playing a dominant role in AD, especially related to the hyperactivation of excitatory neurons. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent kinase and involved in the pathogenesis of AD, but the roles and mechanisms of DAPK1 in excitotoxicity in AD are still uncertain. OBJECTIVE: We mainly explored the underlying mechanisms of DAPK1 involved in the excitotoxicity of AD and its clinical relevance. METHODS: Differentiated SH-SY5Y human neuroblastoma cells, PS1 V97 L transgenic mice, and human plasma samples were used. Protein expression was assayed by immunoblotting, and intracellular calcium and neuronal damage were analyzed by flow cytometry. Plasma DAPK1 was measured by ELISA. RESULTS: We found that DAPK1 was activated after amyloid-ß oligomers (AßOs) exposure in differentiated SH-SY5Y cells. Besides, we found the phosphorylation of GluN2B subunit at Ser1303 was increased, which contributing to excitotoxicity and Ca2+ overload in SH-SY5Y cells. Inhibiting DAPK1 activity, knockdown of DAPK1 expression, and antagonizing GluN2B subunits could effectively prevent AßOs-induced activation of GluN2B subunit, Ca2+ overload, and neuronal apoptosis. Additionally, we found that DAPK1 was elevated in the brain of AD transgenic mouse and in the plasma of AD patients. CONCLUSION: Our finding will help to understand the mechanism of DAPK1 in the excitotoxicity in AD and provide a reference for the diagnosis and therapy of AD.

CaMKIIα Signaling Is Required for the Neuroprotective Effects of Dl-3-n-Butylphthalide in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease and most anti-AD drugs have failed in clinical trials; hence, it is urgent to find potentially effective drugs against AD. DL-3-n-butylphthalide (NBP) is a compound extracted from celery seed and is a multiple-target drug. Several studies have demonstrated the neuroprotective effects of NBP on cognitive impairment, but the mechanisms of NBP remains relatively unexplored. In this study, we found that NBP could alleviated the increase of intracellular Ca2+ and reversed down-regulation of Ca2+/calmodulin-dependent protein kinase alpha (CaMKIIα) signaling and rescued neuronal apoptosis in SH-SY5Y cells treated by Aß oligomers. However, these neuroprotective effects of NBP on neuronal damage and CaMKIIα signaling were abolished when CaMKIIα expression was knocked down or its activity was inhibited. Thus, our findings suggested that CaMKIIα signaling was required for the neuroprotective effects of NBP in AD and provided an improved basis for elucidating the mechanism and treatment of NBP in AD.

Honokiol Restores Microglial Phagocytosis by Reversing Metabolic Reprogramming.

BACKGROUND: Dysfunction of microglia has been increasingly recognized as a causative factor in Alzheimer's disease (AD); thus, developing medicines capable of restoring microglial functions is critically important and constitutes a promising therapeutic strategy. Honokiol is a natural neuroprotective compound extracted from Magnolia officinalis, which may play roles in AD therapy. OBJECTIVE: This study aimed to evaluate the role and the underlying mechanisms of honokiol in microglial phagocytosis. METHODS: MTT and flow cytometry were used to assess the cell viability and apoptosis, respectively. Phagocytic capacity, mitochondrial reactive oxygen species production, and membrane potential were evaluated using fluorescence microscopy. Seahorse XF24 extracellular flux analyzer was for cell glycolysis and oxidative phosphorylation detection. Mass spectrometry was applied for metabolites measurement. Quantitative real-time polymerase chain reaction and western blotting were performed to detect the mRNA and protein level of PPARγ and PGC1α, respectively. RESULTS: Honokiol alleviated Aß42-induced BV2 neurotoxicity. Honokiol promoted phagocytic efficiency of BV2 cells through reversing a metabolic switch from oxidative phosphorylation to anaerobic glycolysis and enhancing ATP production. Meanwhile, honokiol reduced mitochondrial reactive oxygen species production and elevated mitochondrial membrane potential. Moreover, honokiol increased the expression of PPARγ and PGC1α, which might play positive roles in energy metabolism and microglial phagocytosis. CONCLUSION: In this study, honokiol was identified as an effect natural product capable of enhancing mitochondrial function thus promoting microglial phagocytic function.

Decreased Levels of Insulin-Like Growth Factor-1 Are Associated with Alzheimer's Disease: A Meta-Analysis.

BACKGROUND: Alterations in levels of peripheral insulin-like growth factor-1 (IGF-1) in Alzheimer's disease (AD) have been reported in several studies, and results are inconsistent. OBJECTIVE: We conducted a meta-analysis to investigate the relationship between peripheral and cerebrospinal fluid IGF-1 levels and AD or mild cognitive impairment (MCI). METHODS: A systematic search in PubMed, Medline, Web of Science, Embase, and Cochrane Library was conducted and 18 studies were included. RESULTS: Results of random-effects meta-analysis showed that there was no significant difference between AD patients and healthy control (17 studies; standard mean difference [SMD], -0.01; 95%CI, -0.35 to 0.32) and between MCI patients and healthy control (6 studies; SMD, -0.20; 95%CI, -0.52 to 0.13) in peripheral IGF-1 levels. Meta-regression analyses identified age difference might explain the heterogeneity (p = 0.017). However, peripheral IGF-1 levels were significantly decreased in AD subjects (9 studies; SMD, -0.44; 95%CI, -0.81 to -0.07) and MCI subjects exhibited a decreasing trend (4 studies; SMD, -0.31; 95%CI, -0.72 to 0.11) in studies with sample size≥80. Cerebrospinal fluid IGF-1 levels also significantly decreased in AD subjects (3 studies; SMD, -2.40; 95%CI, -4.36 to -0.43). CONCLUSION: These findings suggest that decreased peripheral and cerebrospinal fluid IGF-1 levels might be a potential marker for the cognitive decline and progression of AD.

Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early-onset Alzheimer's disease.

Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) genes account for the majority of autosomal dominant Alzheimer's disease (AD), with PSEN1 being the most common. We screened these genes for mutations in a Chinese proband from an autosomal dominant early-onset AD pedigree. Early-onset AD is defined as the age at onset of AD < 65 years. A heterozygous variant (c.332G > T) of PSEN1, which results in a missense mutation (p.Gly111Val), was identified. Three prediction programs suggested this mutation was disease causing. When PSEN1 Gly111Val was overexpressed in HEK293/APPswe cells, the ratio of Aß42/Aß40 was significantly increased compared with that of wild-type PSEN1. Our results suggest that this novel PSEN1 Gly111Val mutation may play a pathogenic role in AD.

DAPK1: a Novel Pathology and Treatment Target for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and seriously damages the health of elderly population. Clinical drug research targeting at classic pathology hallmarks, such as amyloid-ß (Aß) and tau protein, failed to achieve effective cognitive improvement, suggesting that the pathogenesis of AD is much complicated, and there are still other unknown and undetermined important factors. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent serine/threonine kinase that plays an important role in various neuronal injury models. Mounting evidence has demonstrated that DAPK1 variants are associated with AD risk. The activation of DAPK1 is also involved in AD-related neurodegeneration in the brain. Exploring the roles of DAPK1 in AD might help us understand the pathogenic mechanisms and find a novel promising therapeutic target in AD. Therefore, in this review, we comprehensively summary the main progress of DAPK1 in the AD studies from genetic risk, neuropathological process, and clinical potential implications.