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.

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, xenobiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and neurodegeneration related to its capabilities as an antioxidant and scavenging of harmful molecules, versus its involvement in oxidative stress and aberrant immune response, depending on NM saturation state and its extracellular release.

Aging is associated with an increasing dysfunction of key brain homeostasis mechanisms and represents the main risk factor across most neurodegenerative disorders. However, the degree of dysregulation and the affectation of specific pathways set apart normal aging from neurodegenerative disorders. In particular, the neuronal metabolism of catecholaminergic neurotransmitters appears to be a specifically sensitive pathway that is affected in different neurodegenerations. In humans, catecholaminergic neurons are characterized by an age-related accumulation of neuromelanin (NM), rendering the soma of the neurons black. This intracellular NM appears to serve as a very efficient quencher for toxic molecules. However, when a neuron degenerates, NM is released together with its load (many undegraded cellular components, transition metals, lipids, antibiotics) contributing to initiate and worsen an eventual immune response, exacerbating the oxidative stress, ultimately leading to the neurodegenerative process. This review focuses on the analysis of the role of NM in normal aging and catecholaminergic metabolism due to its capability as a pro-oxidant and other harmful molecules, versus its involvement in oxidative stress and aberrant immune response, which it is highly dependent on NM saturation state and its extracellular release.

Neuromelanin (NM), a neuronal pigment linked to catecholamine metabolism, has been implicated in both protective and detrimental roles in neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Given the continuity between plasma and cerebrospinal fluid, we aimed to identify and characterize plasma proteins retained by synthetic catecholamine polymers used as neuromelanin analogs. Proteins retained or enriched on these matrices were operationally classified as candidate neuromelanin-binding plasma proteins (cNBPPs). cNBPPs in pooled plasma were identified using an exploratory affinity-proteomics approach with two NM analogs (poly-L-DOPA and poly-noradrenaline). Following stringent washing and LC-MS/MS analysis, the identified proteins were evaluated by structural bioinformatics, Gene Ontology, and protein–protein interaction network analyses. Raw data are available in PRIDE repository (PXD084910), and additional processed data at DOI: https://doi.org/10.4321/repisalud.27499 . We identified 98 cNBPPs, 51 (52%) of which were retained by both NM-analog matrices, suggesting shared physicochemical determinants. cNBPPs were more frequently annotated as glycosylated than non-NBPPs. Abundant cNBPPs were typically larger and displayed increased 3₁₀-helix content, whereas low-abundance cNBPPs exhibited reduced α-helix and increased β-sheet content. Functional enrichment associated cNBPPs with inflammation, immune regulation, complement activation, vascular biology, and amyloid-related processes. cNBPPs included hub proteins such as ApoE and adiponectin, while several served as highly connected network nodes, suggesting links between the cNBPP network and neuroinflammation or protein aggregation. These findings offer a hypothesis-generating perspective on potential relationships between NM and neurodegeneration involving plasma proteins and, potentially, their CSF or brain counterparts. This exploratory affinity-proteomics screening may help prioritize candidates for future mechanistic and diagnostic studies. Graphical Abstract Candidate neuromelanin-binding plasma proteins support a protein-corona model. Plasma affinity proteomics using synthetic neuromelanin (NM) analogs identified structurally selective candidate neuromelanin-binding plasma proteins (cNBPPs). Their enrichment in complement, vascular, extracellular proteostasis, and amyloid-related pathways supports a protein-corona hypothesis in which extracellular NM may recruit compatible proteins with potential relevance to neurodegeneration