Abstract
Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinnings of age-related brain changes are still not well understood, particularly the transition from normal healthy brain aging to neuropathological aging. Aging is an extremely complex, multifactorial process involving the simultaneous interplay of several processes operating at many levels of the functional organization. The buildup of potentially toxic protein aggregates and their spreading through various brain regions has been identified as a major contributor to these pathologies. One of the most striking morphologic changes in neurons during normal aging is the accumulation of lipofuscin (LF) aggregates, as well as, neuromelanin pigments. LF is an autofluorescent lipopigment formed by lipids, metals and misfolded proteins, which is especially abundant in nerve cells, cardiac muscle cells and skin. Within the Central Nervous System (CNS), LF accumulates as aggregates, delineating a specific senescence pattern in both physiological and pathological states, altering neuronal cytoskeleton and cellular trafficking and metabolism, and being associated with neuronal loss, and glial proliferation and activation. Traditionally, the accumulation of LF in the CNS has been considered a secondary consequence of the aging process, being a mere bystander of the pathological buildup associated with different neurodegenerative disorders. Here, we discuss recent evidence suggesting the possibility that LF aggregates may have an active role in neurodegeneration. We argue that LF is a relevant effector of aging that represents a risk factor or driver for neurodegenerative disorders.
Highlights
Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinning of age-related brain changes is still not well understood (Kukull et al, 2002)
The most relevant group of disorders clearly related with LF deposits are the neuronal ceroid lipofuscinoses (NCLs)
Neurodegeneration and LF accumulation clearly correlate in most animal models, in this progranulin deficiency mouse model, it has been shown that deletion of the TMEM106B (Transmembrane protein 106B) gene normalizes lysosomal activity and rescues FTD-related behavioral abnormalities and retinal degeneration, without showing a decrease in LF accumulation (Klein et al, 2017); suggesting that neurodegeneration and lipofuscinogenesis are independent processes
Summary
Despite aging being by far the greatest risk factor for highly prevalent neurodegenerative disorders, the molecular underpinning of age-related brain changes is still not well understood (Kukull et al, 2002). Physiological changes associated with aging are inherent to all animals, representing an extremely complex and multifactorial process involving the simultaneous interplay of several processes operating at many levels of the functional organization
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