An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration

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.

Keywords: aging; amyloid; autofluorescence; lipofuscin; neurodegeneration; oxidative stress; protein deposits.

Figure 1

Confocal fluorescence microscopy analysis of AD brain tissue. The characteristic perinuclear lipofuscin deposits can be clearly identified in brain tissue by autofluorescent emission at 510–530 nm (A, green) and at 570–600 nm (B, red), with excitation at 488 nm and 561 nm, respectively. Additionally, amyloid beta plaques (C, white) were immunostained by the specific monoclonal antibody 4G8 (Covance) followed by an anti-antibody conjugated to a fluorophore excitable to 633 nm and emitting light from 670 to 700 nm (Invitrogen GAM-A-21052). DNA in nuclear domains was identified by DAPI probe (D, blue). In the merged image (E), lipofuscin aggregates (pink-orange) appears widely distributed throughout the tissue with incidental colocalization within the amyloid beta plaques. Images represent a single confocal plane of cryosections of prefrontal cortex from an AD patient treated with 70% formic acid for 10 s. The yellow arrows indicate LF aggregates that are located within senile plaques. Adapted with permission from chapter 31 “Characterization of Amyloid-β Plaques and Autofluorescent Lipofuscin Aggregates in Alzheimer's Disease Brain: A Confocal Microscopy Approach” in Amyloid Proteins. Methods and Protocols, Volume 1179 in Methods Molecular Biology Series (ISBN: 978-1-4939-7815-1); Series Ed.: Walker, John M. Humana Press-Springer.

Figure 2

Schematic representation of the role of LF at different points of cellular physiology. With aging, the levels of oxidative stress increase, causing the impairment of several interconnected cellular homeostatic pathways such as the endolysosomal and mitochondrial systems and leading to defective proteostasis, incomplete mitophagy and the activation of lipofuscinogenesis. On the one hand, lipofuscin accumulation harms the proteostasis pathway, further promoting oxidative stress, energetic imbalance, and increased lipofuscinogenesis. On the other hand, altered proteostasis together with endolysosomal dysfunction also obstruct the clearance of misfolded proteins, which may accumulate as seeds for protein aggregation contributing to neurodegeneration. As protein aggregates deposits within the brain tissue, LF formation also increases, hindering both vesicle trafficking and cellular physiology. Finally, as the cell is unable to deal with the cascade of damaging events it degenerates. Upon cell death, LF content is released to the parenchyma, where it can be found associated with pathognomonic protein deposits, such as amyloid beta plaques. These LF deposits recruit cellular debris and metals ions, provoking more oxidative stress, and microglial activation, which triggers neuroinflammation and proinflammatory interleukin production, thus contributing to expanding the neurodegeneration.