Hippocampal overexpression of SGK1 ameliorates spatial memory, rescues Aβ pathology and actin cytoskeleton polymerization in middle-aged APP/PS1 mice

Lian, Biyao; Liu, Mengying; Zhen, Linlin; Sun, Tao; Meng, Ziqi; Chang, Qing; Li, Zhi; Zhang, Jiqiang; Zhao, Caidan

doi:10.1016/j.bbr.2020.112503

Cited by 15 publications

(13 citation statements)

References 49 publications

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“…In addition, the SAK3 administration upregulated serum-and glucocorticoid-induced protein kinase 1 (SGK1) in NL-F mice [17]. SGK1 mediated the Aβ metabolism [50,51] and the overexpression of SGK1 in the hippocampus recues Aβ pathology in APP/PS1 mice [52]. We assumed that both SGK1 upregulation and increase in proteasome activity would account for the reduction in Aβ plaque size induced by SAK3 administration.…”

Section: Discussionmentioning

confidence: 99%

SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling

Izumi

Kawahata

Shinoda

et al. 2020

IJMS

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Alzheimer’s disease (AD) is the most common form of dementia and is characterized by neuropathological hallmarks consisting of accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT). Recently, we have identified a new AD therapeutic candidate, ethyl-8′-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3′-imidazo [1,2-a] pyridin]-2-ene-3-carboxylate (SAK3), which ameliorates the AD-like pathology in AppNL-F/NL-F knock-in mice. However, the detailed mechanism underlying the therapeutic effects of SAK3 remains unclear. In this study, we found that SAK3 administration improved the reduced proteasome activity through the activation of CaMKII/Rpt6 signaling in AppNL-F/NL-F knock-in (NL-G-F) mice. Moreover, spine abnormalities observed in NL-G-F mice were significantly reversed by SAK3 administration. Along with this, cognitive impairments found in NL-G-F mice were markedly ameliorated by SAK3. In summary, our data suggest that SAK3 administration increases the activity of the proteasome via activation of the CaMKII/Rpt6 signaling pathway, contributing to improvements in spine abnormalities and cognitive deficits in NL-G-F mice. Overall, our findings suggest that SAK3 might be a new attractive drug candidate, representing a new mechanism for the treatment of AD pathology.

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Section: Discussionmentioning

confidence: 99%

SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling

Izumi

Kawahata

Shinoda

et al. 2020

IJMS

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Section: Small Molecule Peptide and Protein Mediators And Inhibitors ...mentioning

confidence: 99%

“…Serum- and glucocorticoid-inducible kinase 1 is a member of the Ser/Thr protein kinase family and is involved in spatial memory formation and consolidation in the hippocampus ( Lian et al, 2020 ). A recent study revealed a lack of SGK1 in AD model mice; overexpression of SGK1 in the hippocampus of these mice directly resulted in improved memory ( Lian et al, 2020 ). SGK1 overexpression increased the number of neurites and shortened the time required for neurite formation in hippocampal neurons, in addition to a reduction of Aβ plaques as a result of an increase in Aβ degradase expression ( Lian et al, 2020 ).…”

Section: Small Molecule Peptide and Protein Mediators And Inhibitors ...mentioning

confidence: 99%

Cytoskeletal dysregulation and neurodegenerative disease: Formation, monitoring, and inhibition of cofilin-actin rods

Wurz

Schulz

O’Bryant

et al. 2022

Front. Cell. Neurosci.

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The presence of atypical cytoskeletal dynamics, structures, and associated morphologies is a common theme uniting numerous diseases and developmental disorders. In particular, cytoskeletal dysregulation is a common cellular feature of Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. While the numerous activators and inhibitors of dysregulation present complexities for characterizing these elements as byproducts or initiators of the disease state, it is increasingly clear that a better understanding of these anomalies is critical for advancing the state of knowledge and plan of therapeutic attack. In this review, we focus on the hallmarks of cytoskeletal dysregulation that are associated with cofilin-linked actin regulation, with a particular emphasis on the formation, monitoring, and inhibition of cofilin-actin rods. We also review actin-associated proteins other than cofilin with links to cytoskeleton-associated neurodegenerative processes, recognizing that cofilin-actin rods comprise one strand of a vast web of interactions that occur as a result of cytoskeletal dysregulation. Our aim is to present a current perspective on cytoskeletal dysregulation, connecting recent developments in our understanding with emerging strategies for biosensing and biomimicry that will help shape future directions of the field.

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“…The highest-ranking hippocampal gene, PFN1 (Figure 6A and Table 1), encodes an actin-monomer binding protein that is known to regulate the cytoskeleton of neurites (Murk et al, 2012), but has also been shown to support the highly mobile F-actin in astrocytic projections that surround synaptic clefts (Schweinhuber et al, 2015). It has been associated with impaired synaptic plasticity and spatial memory in the APP/PS1 mouse model of AD (Sun et al, 2019;Lian et al, 2020). Alterations to the function of PFN1 due to AD risk mutations could account for alterations in synaptic maintenance, leading to increased glutamate signaling to extra-synaptic NMDARs.…”

Section: Multiple High-ranking Genes Influence Synaptic Structure Thrmentioning

confidence: 99%

System-Level Analysis of Alzheimer’s Disease Prioritizes Candidate Genes for Neurodegeneration

et al. 2021

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Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder. Since the advent of the genome-wide association study (GWAS) we have come to understand much about the genes involved in AD heritability and pathophysiology. Large case-control meta-GWAS studies have increased our ability to prioritize weaker effect alleles, while the recent development of network-based functional prediction has provided a mechanism by which we can use machine learning to reprioritize GWAS hits in the functional context of relevant brain tissues like the hippocampus and amygdala. In parallel with these developments, groups like the Alzheimer’s Disease Neuroimaging Initiative (ADNI) have compiled rich compendia of AD patient data including genotype and biomarker information, including derived volume measures for relevant structures like the hippocampus and the amygdala. In this study we wanted to identify genes involved in AD-related atrophy of these two structures, which are often critically impaired over the course of the disease. To do this we developed a combined score prioritization method which uses the cumulative distribution function of a gene’s functional and positional score, to prioritize top genes that not only segregate with disease status, but also with hippocampal and amygdalar atrophy. Our method identified a mix of genes that had previously been identified in AD GWAS including APOE, TOMM40, and NECTIN2(PVRL2) and several others that have not been identified in AD genetic studies, but play integral roles in AD-effected functional pathways including IQSEC1, PFN1, and PAK2. Our findings support the viability of our novel combined score as a method for prioritizing region- and even cell-specific AD risk genes.

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Hippocampal overexpression of SGK1 ameliorates spatial memory, rescues Aβ pathology and actin cytoskeleton polymerization in middle-aged APP/PS1 mice

Cited by 15 publications

References 49 publications

SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling

SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling

Cytoskeletal dysregulation and neurodegenerative disease: Formation, monitoring, and inhibition of cofilin-actin rods

System-Level Analysis of Alzheimer’s Disease Prioritizes Candidate Genes for Neurodegeneration

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