Neuronal pigmented autophagic vacuoles: lipofuscin, neuromelanin, and ceroid as macroautophagic responses during aging and disease

Abstract

The most striking morphologic change in neurons during normal aging is the accumulation of autophagic vacuoles filled with lipofuscin or neuromelanin pigments. These organelles are similar to those containing the ceroid pigments associated with neurologic disorders, particularly in diseases caused by lysosomal dysfunction. The pigments arise from incompletely degraded proteins and lipids principally derived from the breakdown of mitochondria or products of oxidized catecholamines. Pigmented autophagic vacuoles may eventually occupy a major portion of the neuronal cell body volume because of resistance of the pigments to lysosomal degradation and/or inadequate fusion of the vacuoles with lysosomes. Although the formation of autophagic vacuoles via macroautophagy protects the neuron from cellular stress, accumulation of pigmented autophagic vacuoles may eventually interfere with normal degradative pathways and endocytic/secretory tasks such as appropriate response to growth factors.

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation

“…The positive linear correlation between age and the LB area proportion in human and non-human primate beta cells is similar to data derived from LB distribution in post-mitotic cells in other organs such as the human brain [23,29,30] and rat cardiac myocytes and neurons [24,31,32] and extends the observations made previously on 'lipid-storing vesicles' [26]. Lipofuscin is similar in appearance to ceroid, which accumulates rapidly as a result of pathological conditions such as neurodegenerative and genetic diseases but is not age-related [33].…”

The pathology roadmap in Parkinson disease

“…These two nuclei exhibit the greatest loss in PD. Nevertheless, some highly pigmented A2 catecholaminergic, neuromelanin-positive neurons in the caudal medulla do not appear to be lost in PD, 32 and so neuromelanin synthesis per se, which may be a neuroprotective response, 63,64 is not sufficient for neuronal death. In the periphery, the loss of NE neurons is variable, with some sympathetic neurons appearing to be vulnerable and others not.…”

“…103 Lysosomes and autophagic vacuoles that deliver intracellular components to lysosomes, key elements in the catabolic machinery, are dependent upon calcium signaling for their regulation 104 and are potential sites of ROS generation. 64 A number of genes linked to PD have effects on lysosomal function as well. 105 These observations raise the possibility that proteostatic challenges that increase lysosomal activity could exacerbate basal oxidant stress in vulnerable neurons, promoting degeneration.…”

Parahippocampal corpora amylacea and neuronal lipofuscin in human aging

“…Both pigments have been until recently considered as inert waste products of neural tissue components of little interest to the neuroscience community. Lipofuscin is a protein and lipid-based pigment with broad distribution [32,33]. Another term found in the literature for lipofuscin is "ceroid".…”

“…Based on its prevalence in motor areas and the cerebral cortex, it might be assumed that it is involved in the changes in motor fidelity and cognitive decline that accompany aging. This hypothesis is predicated on the existence of a deleterious influence of lipofuscin accumulation during the inherited, fatal neurological disorders known as the neuronal ceroid lipofuscinoses [33,44].…”