<scp>LINGO</scp>‐1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5<scp>XFAD</scp> mice

Wu, Di; Xiang, Tao; Gu, Lihua; Li, Xiaoli; Qi, Xinyang; Bai, Feng; Chen, Xiaochun; Wang, Jian‐Zhi; Ren, Qiangqiang; Zhang, Zhijun

doi:10.1111/cns.12809

Cited by 41 publications

(50 citation statements)

References 39 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Richard et al, reported in this last line of 5xFAD spatial memory de cits were only visible after 7 months of age (73). Others reported spatial memory impairment at an earlier age when using the water maze but with a very small difference between WT and 5xFAD (74,75).. In the present study, none of the groups tested in the SYM test performed above chance level indicating lack of recognition in all groups examined.…”

Section: Discussionsupporting

confidence: 45%

CERTL reduces C16 ceramide, amyloid-β levels and inflammation in a model of Alzheimer's disease

Crivelli

Luo

Stevens

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety and locomotion. At week twelve, brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTL in vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

show abstract

Section: Discussionsupporting

confidence: 45%

CERTL reduces C16 ceramide, amyloid-β levels and inflammation in a model of Alzheimer's disease

Crivelli

Luo

Stevens

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…We found a statistically significant CAW treatment-dependent increase in these synaptic markers in the cortex, while there was a significant increase in synaptophysin in the hippocampus and an increasing trend in Psd95 (p=0.026) with CAW treatment. An interesting observation in the progression of 5XFAD pathology is that spine loss (4-9 months) [62] occurs subsequent to cognitive dysfunction (3-6 months) [35,[63][64][65][66] and Aβ plaque formation (two months) [67]. This is different from the progression in Tg2576, which manifests synaptic damage at an early stage of pathological development (4.5 months) [68,69] with a corresponding decrease in synaptic density markers [70] prior to Aβ plaque development (10 months) [71] and cognitive deficiencies (one year) [72,73].…”

Section: Discussionmentioning

confidence: 99%

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

et al. 2019

View full text Add to dashboard Cite

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer’s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ − 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW’s impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

show abstract

“…In contrast, in the current studies, the 6-month-old 5xFAD mice displayed impairment of social recognition memory but not spatial memory. While memory impairment in this 5xFAD mouse strain has been detected as young as 1 month of age through the Morris water maze [493], [494], others have found that 5xFAD mice display normal spatial memory function in this test until 7 months of age [238] or even up to 12 months of age [495]. Likewise, recognition memory has been shown to emerge at 4 months of age [495] in one study and at 9 months of age in another [468].…”

Section: Discussionmentioning

confidence: 94%

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

Ringland

Schweig

Paris

et al. 2020

Neurobiology of Aging

View full text Add to dashboard Cite

Apolipoprotein E (APOE) is a major genetic risk factor for Alzheimer's disease (AD) and has been shown to influence amyloid-β (Aβ) clearance from the brain in an isoform-specific manner. Our prior work showed Aβ transit across the blood-brain-barrier was reduced by apoE4, compared to other apoE isoforms, due to elevated lipoprotein receptor shedding in brain endothelia. Recently, we demonstrated matrix metallopeptidase 9 (MMP-9) induces lipoprotein receptor proteolysis in an apoE isoform-dependent manner, which impacts Aβ elimination from the brain. The current studies interrogated the relationship between apoE and MMP-9 and found apoE dose-dependently reduced MMP-9 activity in a cell-free assay, with apoE4 showing a significantly weaker ability to inhibit MMP-9 function than apoE2 or apoE3. Moreover, these effects may be due to the reduced binding affinity of apoE4 for MMP-9 compared to apoE2 and apoE3 as revealed by kinetic binding studies. Elevated MMP-9 expression and activity was observed in the cerebrovasculature of both human and animal AD brain specimens with an APOE4 genotype. The apoE isoforms also lead to altered levels of MMP-9 secreted from brain endothelia cultures (apoE2

show abstract

LINGO‐1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice

Cited by 41 publications

References 39 publications

CERTL reduces C16 ceramide, amyloid-β levels and inflammation in a model of Alzheimer's disease

CERTL reduces C16 ceramide, amyloid-β levels and inflammation in a model of Alzheimer's disease

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

Apolipoprotein E isoforms differentially regulate matrix metallopeptidase 9 function in Alzheimer’s disease

Contact Info

Product

Resources

About