The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction.
The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction.
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衰老是大多数神经退行性疾病的主要风险因素，包括阿尔茨海默病。大脑老化的主要标志包括神经炎症/免疫激活和神经元健康/功能下降。这些过程导致认知功能障碍（阿尔茨海默病的一个关键风险因素），但其上游原因尚未完全了解。转座因子（TE）转录物的年龄相关性增加可能导致认知功能随着大脑老化而降低，因为逆转录酶抑制剂3 TC减少了外周组织中的炎症，并且TE转录物与阿尔茨海默病中的tau病理学有关。然而，3 TC对认知功能随年龄增长的影响尚未研究。在这里，为了支持TE转录物在脑老化/认知下降中的作用，我们表明3 TC：（a）改善老年野生型小鼠的认知功能并减少神经炎症;（B）在小鼠和秀丽隐杆线虫中随着衰老保持神经元健康;（c）增强tau蛋白病小鼠模型的认知功能。我们还提供了关于潜在潜在机制的见解，以及这些观察结果的翻译相关性证据，表明TE转录物随着人类大脑衰老而积累，并且这些年龄相关的增加与阿尔茨海默病中观察到的增加相交。总的来说，我们的研究结果表明，在衰老过程中TE转录物的积累可能会导致认知能力下降和神经退行性变，并且用逆转录酶抑制剂如3 TC靶向这些事件可能是一种可行的治疗策略。转座因子转录物的年龄相关性增加可能通过刺激神经炎症而导致脑老化和神经退行性变。用逆转录酶抑制剂3 TC靶向这些转录物有可能通过减少免疫激活/神经炎症来改善认知功能。
Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age‐related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild‐type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age‐related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy. Age‐related increases in transposable element transcripts may contribute to brain aging and neurodegeneration by stimulating neuroinflammation. Targeting these transcripts with the reverse transcriptase inhibitor 3TC has the potential to improve cognitive function by reducing immune activation/neuroinflammation.
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影响因子：
10.1
作者：
D'Alessandro A;Fu X;Kanias T;Reisz JA;Culp-Hill R;Guo Y;Gladwin MT;Page G;Kleinman S;Lanteri M;Stone M;Busch MP;Zimring JC;Recipient Epidemiology and Donor Evaluation Study-III (REDS III)
通讯作者：
Recipient Epidemiology and Donor Evaluation Study-III (REDS III)
影响因子：
6.8
作者：
Chatterjee P;Pedrini S;Stoops E;Goozee K;Villemagne VL;Asih PR;Verberk IMW;Dave P;Taddei K;Sohrabi HR;Zetterberg H;Blennow K;Teunissen CE;Vanderstichele HM;Martins RN
通讯作者：
Martins RN
影响因子：
5.7
作者：
Corlier F;Hafzalla G;Faskowitz J;Kuller LH;Becker JT;Lopez OL;Thompson PM;Braskie MN
通讯作者：
Braskie MN
影响因子：
9.8
作者：
De Jager, Philip L.;Ma, Yiyi;Bennett, David A.
通讯作者：
Bennett, David A.
影响因子：
5.7
作者：
Cardenas-Tueme, Marcela;Angel Trujillo-Villarreal, Luis;Resendez-Perez, Diana
通讯作者：
Resendez-Perez, Diana