Dcf1 alleviates C99-mediated deficits in drosophila by reducing the cleavage of C99

Li, Weihao; Li, Yanhui; Gan, Linhua; Ma, Feifei; Zhang, Shibo; Wen, Tao

doi:10.1016/j.bbrc.2020.05.063

Cited by 2 publications

(2 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, TMEM59 overexpression had no effect on Aβ40 and Aβ42 levels in TBS-and TBSX-soluble fractions, implying that TMEM59 overexpression may not affect Aβ generation. This finding is in contrast to previous studies showing that TMEM59 overexpression could inhibit APP glycosylation and cell surface expression, as well as the cleavage of APP to generate Aβ in HEK293 cells (Ullrich et al, 2010), and that TMEM59 overexpression could reduce the γ-cleavage of APP C99 fragment and promote learning and memory in C99 transgenic drosophila (Li et al, 2020). Although our finding that APP glycosylation was increased in 5xFAD mice with TMEM59 haploinsufficiency is consistent with the observation that TMEM59 overexpression inhibited APP glycosylation (Ullrich et al, 2010), TMEM59 haploinsufficency had no effect on levels of total APP, APP α-/β-CTF, and soluble Aβ in vivo.…”

Section: Discussioncontrasting

confidence: 99%

“…Microarray data analysis also revealed that TMEM59 gene expression was higher in AD patients than in controls (Guttula et al, 2012). Very recently another study reported that overexpression of TMEM59 reduced the cleavage of APP C99 fragment by γ-secretase and promoted learning and memory in drosophila expressing APP C99 (Li et al, 2020). All these studies suggest that TMEM59 is associated with AD.…”

Section: Introductionmentioning

confidence: 84%

See 1 more Smart Citation

TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer’s Disease

Jian

Han

Zheng

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with cognitive deficits and synaptic impairments. Amyloid-β (Aβ) plaque deposition, dystrophic neurite accumulation and neurofibrillary tangles are pathological hallmarks of AD. TMEM59 has been implicated to play a role in AD pathogenesis; however, the underlying mechanism remains unknown. Herein, we found that overexpression of TMEM59 in the hippocampal region led to memory impairment in wild type mice, suggesting its neurotoxic role. Interestingly, while TMEM59 overexpression had no effect on worsening synaptic defects and impaired memory in the 5xFAD mouse model of AD, it significantly exacerbated AD-like pathologies by increasing levels of detergent-insoluble Aβ and Aβ plaques, as well as dystrophic neurites. Importantly, haploinsufficiency of TMEM59 reduced insoluble Aβ levels, Aβ plaques, and neurite dystrophy, thereby rescuing synaptic plasticity and memory deficits in 5xFAD mice. Moreover, the level of TMEM59 in the brain of 5xFAD mice increased compared to wild type mice during aging, further corroborating its detrimental functions during neurodegeneration. Together, these results demonstrate a novel function of TMEM59 in AD pathogenesis and provide a potential therapeutic strategy by downregulating TMEM59.

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 84%

TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer’s Disease

Jian

Han

Zheng

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

Deletion of Dcf1 Reduces Amyloid-β Aggregation and Mitigates Memory Deficits

Gan

et al. 2021

JAD

View full text Add to dashboard Cite

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-β (Aβ) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aβ aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients. Objective: Our goal is to investigate the effect of Dcf1 on Aβ aggregation and memory deficits in AD development. Methods: The mouse and Drosophila AD model were used to test the expression and aggregation of Aβ, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies. Results: Deletion of Dcf1 resulted in decreased Aβ42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aβ42 AD Drosophila, the expression of Dcf1 in Aβ42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aβ aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice. Conclusion: Dcf1 causes Aβ-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues.

show abstract

Dcf1 alleviates C99-mediated deficits in drosophila by reducing the cleavage of C99

Cited by 2 publications

References 34 publications

TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer’s Disease

TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer’s Disease

Deletion of Dcf1 Reduces Amyloid-β Aggregation and Mitigates Memory Deficits

Contact Info

Product

Resources

About