scholarly journals Effects of Specific Inhibitors for CaMK1D on a Primary Neuron Model for Alzheimer’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7669
Author(s):  
Paige Grant ◽  
Jitendra Kumar ◽  
Satyabrata Kar ◽  
Michael Overduin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Cortical Neurons ◽  
Kinase Inhibitors ◽  
Tau Hyperphosphorylation ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
Molecular Components ◽  
Specific Inhibitors

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aβ) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aβ-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aβ induced tau hyperphosphorylation in culture, but were not able to protect cells from Aβ induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD.

scholarly journals Loss of function of the mitochondrial peptidase PITRM1 induces proteotoxic stress and Alzheimer’s disease-like pathology in human cerebral organoids

2020 ◽  
Author(s):  
Dina Ivanyuk ◽  
María José Pérez ◽  
Vasiliki Panagiotakopoulou ◽  
Gabriele Di Napoli ◽  
Dario Brunetti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Cortical Neurons ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Protein Aggregates ◽  
Neuronal Cultures ◽  
Loss Of Function ◽  
Proteotoxic Stress

AbstractMutations in pitrilysin metallopeptidase 1 (PITRM1), a mitochondrial protease involved in mitochondrial precursor processing and degradation, result in a slow-progressive syndrome, characterized by cerebellar ataxia, psychotic episodes and obsessive behavior as well as cognitive decline. To investigate the pathogenetic mechanisms of mitochondrial presequence processing, we employed cortical neurons and cerebral organoids generated from PITRM1 knockout human induced pluripotent stem cells (iPSCs). PITRM1 deficiency strongly induced mitochondrial unfolded protein response (UPRmt) and enhanced mitochondrial clearance in iPSC-derived neurons. Furthermore, we observed increased levels of amyloid precursor protein and amyloid β in PITRM1 knockout neurons. However, neither cell death nor protein aggregates were observed in 2D iPSC-derived cortical neuronal cultures. On the contrary, cerebral organoids generated from PITRM1 knockout iPSCs spontaneously developed over time pathological features of Alzheimer’s disease (AD), including accumulation of protein aggregates, tau pathology, and neuronal cell death. Importantly, we provide evidence for a protective role of UPRmt and mitochondrial clearance against impaired mitochondrial presequence processing and proteotoxic stress. In summary, we propose a novel concept of PITRM1-linked neurological syndrome whereby defects of mitochondrial presequence processing induce an early activation of UPRmt that, in turn, modulates cytosolic quality control pathways. Thus our work supports a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies.

scholarly journals Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Yulian Zou ◽  
Chen-Ling Gan ◽  
Zhiming Xin ◽  
Hai-Tao Zhang ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Mouse Models ◽  
Glycogen Synthase ◽  
Neuronal Damage ◽  
Amyloid Β ◽  
Glycogen Synthase Kinase ◽  
Tau Hyperphosphorylation

Alzheimer’s disease (AD) is a central nervous system degenerative disease, with no effective treatment to date. Administration of immune checkpoint inhibitors significantly reduces neuronal damage and tau hyperphosphorylation in AD, but the specific mechanism is unclear. Here, we found that programmed cell death-receptor 1 (PD1) and its ligand PDL1 were induced by an intracerebroventricular injection of amyloid-β; they were significantly upregulated in the brains of APP/PS1, 5×FAD mice and in SH-SY5Y-APP cell line compared with control. The PD1 and PDL1 levels positively correlated with the glycogen synthase kinase 3 beta (GSK3β) activity in various AD mouse models, and the PDL1-GSK3β immune complex was found in the brain. The application of PD1-blocking antibody reduced tau hyperphosphorylation and GSK3β activity and prevented memory impairments. Mechanistically, we identified PD1 as a critical regulator of GSK3β activity. These results suggest that the immune regulation of the PD1/PDL1 axis is closely involved in AD.

scholarly journals Withdrawn: Safranal induces autophagy by AMPK activation and protects neurons against amyloid beta in Alzheimer’s disease

2021 ◽  
Vol 18 (3) ◽  
pp. 459-464
Author(s):  
Xiaocheng Huang ◽  
Manlian Zhu ◽  
Ying Hua ◽  
Xiumei Yan ◽  
Ruilai Jiang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Primary Neurons ◽  
Ampk Activation ◽  
Mtor Inhibition ◽  
Ampk Pathway ◽  
Calcium Calmodulin Dependent ◽  
Intracellular Calcium Level ◽  
Dependent Protein

This article has been withdrawn by the Editor Purpose: To investigate autophagic induction by safranal and neuroprotection against amyloid beta in Alzheimer’s disease. Methods: Primary neurons and SH-SY5Y cells were used in this study. Assessment of cell proliferation and neuroprotection by safranal against amyloid beta was done by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. AMPK activation and mTOR inhibition were determined by western blot. Changes in intracellular calcium level, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were assessed by flow cytometry. Results: Safranal protected neurons against amyloid beta toxicity. Furthermore, safranal activated AMPK pathway by activation of calcium/calmodulin-dependent protein kinase (CaMKKβ) to induce autophagy in both cell lines. The toxicity induced by amyloid beta in primary neurons and SH-SY5Y cells were attenuated by safranal. Moreover, amyloid beta-induced calcium levels were significantly decreased by safranal while ROS and MMP loss produced by amyloid beta was attenuated by safranal. Conclusion: These findings suggest that safranal protects neurons against amyloid beta by inducing autophagy via AMPK pathway. Therefore, safranal is a probable therapeutic target for Alzheimer’s disease.

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