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

Jian Meng,Huaxi Xu,Zhaoji Liu,Hui Xu,Dan Can,Yun-Wu Zhang,Hao Sun,Linkun Han,Naizhen Zheng,Hong Luo,Xian Zhang

doi:10.3389/fcell.2020.596030

Abstract

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.

Highlights

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by abnormal accumulation and deposition of various amyloid-β (Aβ) peptides derived from amyloid-β precursor protein (APP), formation of neurofibrillary tangles containing hyperphosphorylated tau, synaptic dysfunction, neuroinflammation, neuronal death, and cognitive decline (Crews and Masliah, 2010; Huang and Mucke, 2012; Guerreiro and Bras, 2015; Kocahan and Dogan, 2017; DeTure and Dickson, 2019)
At 6–7 months of age, we found that overexpression of Transmembrane protein 59 (TMEM59) in wild type (WT) and 5xFAD; Tmem59+/− (5xFAD) mice did not affect their total moving distance and time spent in the center during open field tests, suggesting that TMEM59 overexpression has no effect on mouse locomotor activity and anxiety (Supplementary Figures 2G,H)
While TMEM59 overexpression had no effect on altering these behaviors in 5xFAD mice, its overexpression in WT mice significantly reduced time spent in the target quadrant during the probe test (Figure 1E)

Summary

Introduction

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by abnormal accumulation and deposition of various amyloid-β (Aβ) peptides derived from amyloid-β precursor protein (APP), formation of neurofibrillary tangles containing hyperphosphorylated tau, synaptic dysfunction, neuroinflammation, neuronal death, and cognitive decline (Crews and Masliah, 2010; Huang and Mucke, 2012; Guerreiro and Bras, 2015; Kocahan and Dogan, 2017; DeTure and Dickson, 2019). One study found that TMEM59 overexpression in cells induced APP retention in the Golgi, thereby inhibiting APP cleavage by α- and β-secretases at the plasma membrane and in the endosomes, respectively, resulting in reduced Aβ production (Ullrich et al, 2010). 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. The exact role of TMEM59 in AD has yet to be fully determined

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Conclusion