LINE-1 Retrotransposon Reactivation Linked to Neuronal Aging and Alzheimer's Disease
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Rusty Gage's team has described a mechanism in which LINE-1 retrotransposons, roughly 40% of the human genome, are held silent in mature neurons inside RNA condensates. With aging these condensates dissolve, freeing LINE-1 RNA to activate cGAS-STING inflammation and drive neuronal senescence, a process implicated in Alzheimer's disease. The work rests on neurons derived from patient fibroblasts in about three weeks, which preserve donor age, supported by a skin biopsy bank covering 150 donors: healthy elderly and Alzheimer's and mild cognitive impairment patients. In vitro, reverse transcriptase inhibitors such as 3TC reduced inflammation in Alzheimer's-derived neurons. Mouse model tests are under way, and Gage expects Alzheimer's-related human trials to begin within about two years.
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Rusty Gage described how LINE-1 retrotransposons, about 40% of the human genome, are silenced in mature neurons as RNA condensates that dissolve with aging, freeing LINE-1 RNA to trigger cGAS-STING inflammation and neuronal senescence. His team derived neurons from patient fibroblasts in about three weeks, preserving donor age, with a skin biopsy bank from 150 healthy elderly and Alzheimer's and mild cognitive impairment donors. Reverse transcriptase inhibitors such as 3TC reduced inflammation in AD-derived neurons in vitro, mouse model tests are under way, and Gage expects AD-related human trials within about two years.
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