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Lipids, the fatty molecules that form cell membranes and serve as energy sources, have long been overlooked in the study of neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), and Lewy body dementia (LBD). Many of these diseases are characterized by the abnormal aggregation and spread of misfolded proteins throughout the brain. The hallmark pathologies of AD are extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein, while PD is characterized by intracellular Lewy bodies and Lewy neurites composed mainly of misfolded α-synuclein. For many years, research has focused heavily on the upstream mechanisms driving abnormal protein aggregation and seeding of these pathologies. However, dysregulated lipid metabolism may be an equally important driver of neurodegenerative disease progression by promoting the spread of protein aggregates between cells.
Lipids play a critical role in neuronal function by forming cellular membranes, facilitating vesicular trafficking, and participating in signaling pathways. However, alterations in lipid composition and metabolism can directly impact protein aggregation and interneuronal transfer of pathogenic seeds. For example, polyunsaturated fatty acids accelerate the oligomerization of α-synuclein into insoluble aggregates compared to saturated fatty acids. The binding of α-synuclein to negatively charged lipids can also induce conformational changes that increase vesicle permeability. Similarly, gangliosides GM1 and GM3 accelerate Aβ aggregation in vitro. These findings indicate bidirectional interactions between lipid membranes and aggregate-prone proteins that can exacerbate pathology.
Beyond direct effects on protein misfolding, lipid alterations critically regulate the biogenesis of extracellular vesicles (EVs) like exosomes that act as vectors transferring pathogenic protein species between cells. The unique lipid composition of EVs, enriched in ceramides, cholesterol, and specific gangliosides, influences EV release, uptake by recipient cells, and aggregation of cargo proteins.Inhibiting neutral sphingomyelinase to reduce ceramide generation impairs exosome secretion and the associated transfer of α-synuclein, while depleting glycosphingolipids prevents Aβ binding and oligomerization. These studies highlight how lipid changes tune the propensity of EVs to promote or limit intercellular protein aggregation transfer.
Mounting evidence from genetic, transcriptomic, and lipidomic studies confirms that lipid metabolism is broadly dysregulated across major neurodegenerative proteinopathies like AD and PD. Analysis of postmortem brain tissue and biofluid samples reveals altered levels of numerous lipid species, including ceramides, sphingolipids, fatty acids, and cholesterol, that correlate with disease risk and severity. Many of the genetic risk factors identified, such as APOE4 in AD and mutations in GBA in PD, directly impair lipid processing and trafficking pathways within neurons.
The strongest evidence linking lipid dysregulation to neurodegenerative disease progression comes from studies of GBA-associated PD. Heterozygous mutations in GBA, encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the most common genetic risk factor for developing PD and are associated with more rapid motor and cognitive decline. Reduced GCase activity leads to accumulation of its substrate glucosylceramide and depletion of downstream ceramide products. This underlies broader defects in lysosomal function and altered lipid composition of cellular membranes.Importantly, reductions in GCase activity and similar lipid disturbances are also observed in sporadic PD cases lacking GBA mutations, highlighting a shared pathogenic mechanism.
Exosomes are small EVs generated through the endosomal pathway as multivesicular bodies fuse with the plasma membrane. Growing evidence implicates exosomes as key mediators of neurodegenerative protein aggregation and spread. Exosomes isolated from the cerebrospinal fluid or brain tissue of PD and AD patients are capable of seeding α-synuclein and Aβ aggregation when introduced to cell cultures or injected into mouse brains. Inhibiting exosome biogenesis through targeting ESCRT machinery or neutral sphingomyelinase reduces the associated transfer of pathogenic proteins between cells. Moreover, the lipid composition of exosomes from diseased patients, enriched in certain ceramide species, appears to enhance the binding and fibrillization of α-synuclein cargo.
The studies in GBA-associated PD models provide some of the most compelling evidence for this pathogenic mechanism. In cultured neurons and rodent models, GBA deficiency leads to increased release of exosomes that promote cell-to-cell transfer of α-synuclein aggregates. Restoring GCase activity in specific tissues normalizes excess exosome secretion and protein aggregation in a non-cell autonomous manner, consistent with a role in limiting aggregate spread. These observations may explain the more aggressive clinical course and accelerated brain propagation of synucleinopathy in GBA mutation carriers.
While much research has focused on neuron-to-neuron transmission, emerging data suggests glial cells like astrocytes and microglia play an active role in the uptake, processing, and propagation of pathogenic protein aggregates associated with exosomes or other EVs. Astrocytes appear to preferentially internalize α-synuclein, Aβ, and tau aggregates compared to neurons due to more efficient endocytic machinery. However, these proteins may resist degradation in astrocytes, accumulating in dysfunctional lysosomes and stimulating the release of neurotoxic astrocytic exosomes containing ceramide-enriched membranes that seed further aggregation.
Microglia exhibit neuroprotective functions by phagocytosing and clearing extracellular protein aggregates. Yet microglial exosomes can also propagate α-synuclein, Aβ, and tau pathology by transferring partially degraded cargo to neighboring neurons upon internalization. In essence, glial cells may represent a double-edged sword that protects against but also potentially exacerbates pathogenic protein spread depending on their capacity to degrade internalized aggregates or package them into neurotoxic EVs.
The role of dysfunctional lipid metabolism in neurodegenerative diseases underscores the need to develop therapies targeting these pathways, either alone or in combination with approaches tackling upstream proteinopathies. Several studies demonstrate that interventions modulating lipid levels, such as reducing glucosylceramide accumulation or blocking ceramide production, can ameliorate pathology in cell and animal models of PD and AD. Compounds that modulate exosome biogenesis and release by targeting the ESCRT pathway or neutral sphingomyelinases may limit intercellular transfer of misfolded proteins.
An alternative approach could leverage glial cells' increased propensity to internalize pathogenic protein aggregates. Strategies to boost glial degradation capacity through lysosomal biogenesis or augment their phagocytic clearance activities could provide a therapeutic sink to restrict spread. However, such interventions would need to be coupled with mechanisms preventing glial cells from releasing partially degraded aggregates in neurotoxic EVs.
Finally, lipidomic profiling in biofluids like cerebrospinal fluid or serum could yield biomarkers reflecting central versus systemic lipid dysregulation. Specific lipid signatures may predict the risk and rate of disease progression, enabling enrichment of clinical trials for therapies targeting these pathways. Ultimately, a multi-pronged strategy harnessing complementary approaches that mitigate both upstream proteinopathies and resulting downstream consequences like lipid disturbances may prove most effective at halting neurodegenerative diseases.
Alterations in lipid homeostasis promote pathogenic protein aggregation, facilitate intercellular transmission via exosomes and other EVs, and modulate glial responses that potentially exacerbate spread. These processes are deeply intertwined across multiple neurodegenerative proteinopathies, with particularly compelling evidence stemming from GBA-associated Parkinson's disease. As our understanding of these mechanisms grows, new therapeutic opportunities are emerging focused on restoring lipid balance, intercepting neurotoxic EVs, and harnessing glial defenses.