Il gene APOE4 è collegato a meccanismi potenzialmente reversibili di danno ai vasi sanguigni cerebrali nella malattia di Alzheimer. / APOE4 Linked to Potentially Reversible Mechanisms of Brain Blood Vessel Damage in Alzheimer’s

Il gene APOE4 è collegato a meccanismi potenzialmente reversibili di danno ai vasi sanguigni cerebrali nella malattia di Alzheimer.  / APOE4 Linked to Potentially Reversible Mechanisms of Brain Blood Vessel Damage in Alzheimer’s

Segnalato dal Dott. Giuseppe Cotellessa / Reported by Drs. Giuseppe Cotellessa

I dati provenienti da due studi che utilizzano modelli di tessuto cerebrale e topi anziani contribuiscono a spiegare come l'APOE4, un fattore di rischio genetico per la malattia di Alzheimer, danneggi i vasi sanguigni del cervello e promuova l'accumulo di proteine ​​anomale. I risultati sono stati pubblicati in due articoli sulle riviste Cell e Cell Stem Cell . L' articolo su Cell si intitola " Una transizione da pericita a miofibroblasto collega l'APOE4 alla degenerazione cerebrovascolare ". L' articolo su Cell Stem Cell si intitola " La disregolazione del colesterolo negli astrociti APOE4 promuove la patologia dell'α-sinucleina nei miBrains ".

Entrambi gli studi sono condotti da scienziati della Icahn School of Medicine del Mount Sinai. Essi contribuiscono a rispondere a domande sul meccanismo esatto con cui i vasi sanguigni si deteriorano con il progredire dell'Alzheimer, in particolare nelle persone portatrici del gene APOE4. Lo studio pubblicato su Cell descrive in dettaglio come i ricercatori del Mount Sinai abbiano combinato set di dati preesistenti per creare un atlante trascrittomico a singola cellula del sistema vascolare del cervello umano, ottenendo una mappa dettagliata dell'attività genica nelle cellule che formano e sostengono i vasi sanguigni. 

Questi dispositivi mimano anche il comportamento dei cervelli umani portatori dell'allele APOE4. Nello specifico, i miBrain portatori di APOE4 accumulano livelli più elevati di alfa-sinucleina anomala, la proteina comunemente associata alla demenza a corpi di Lewy ed al morbo di Parkinson. Gli esperimenti descritti nell'articolo hanno dimostrato che l'APOE4 causa l'accumulo di colesterolo negli astrociti e che questo eccesso di colesterolo compromette il sistema lisosomiale di smaltimento dei rifiuti degli astrociti, riducendo la loro capacità di degradare l'alfa-sinucleina. La proteina, invece, si aggrega e si diffonde ai neuroni, portando alla formazione di depositi proteici dannosi. I risultati identificano il metabolismo del colesterolo negli astrociti e la funzione lisosomiale come promettenti bersagli terapeutici per il morbo di Alzheimer ed il morbo di Parkinson.

"Un progresso fondamentale della nostra tecnologia è la possibilità di crioconservare i miBrain con composizioni cellulari predefinite e fattori correlati alla malattia", ha affermato Louise Mesentier-Louro, PhD, professoressa associata di neuroscienze, biologia delle cellule staminali e medicina rigenerativa al Mount Sinai e prima autrice dello studio. "Questa capacità migliora la riproducibilità e la scalabilità della modellazione di malattie complesse e supporta uno sviluppo e una validazione dei farmaci più efficienti."

ENGLISH

Data from two studies using models of brain tissue and aged mice help explain how APOE4, a genetic risk factor for Alzheimer’s disease, damages the brain’s blood vessels and promotes the buildup of abnormal protein. The findings are published in two papers in the journals Cell and Cell Stem Cell. The Cell paper is titled “A pericyte-to-myofibroblast transition links APOE4 to cerebrovascular degeneration.” The Cell Stem Cell paper is titled “Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains.”

Both studies are led by scientists at the Icahn School of Medicine at Mount Sinai. They help answer questions about the exact mechanism by which blood vessels deteriorate as Alzheimer’s progresses, particularly in people with APOE4. The Cell study details how the Mount Sinai researchers combined existing datasets to create a single-cell transcriptomic atlas of the human brain’s vasculature, resulting in a detailed map of gene activity across cells that form and support blood vessels. 

By analyzing the map, they found that APOE4 caused pericytes, which are cells that stabilize small blood vessels and help maintain the blood-brain barrier, to transform into scar-forming myofibroblast-like cells. This change promoted vascular fibrosis and increased amyloid accumulation around the vessels. This created conditions that may compromise blood flow and promote neurodegeneration. Using aged APOE4 mice, the scientists observed the effects of blocking TGF-β signaling, a pathway involved in cellular communication and tissue remodeling. They found that it restored pericyte coverage and reduced both fibrosis and vascular amyloid, effectively demonstrating that it may be possible to reverse APOE4-associated cerebrovascular degeneration therapeutically.

These results show that “damage to the brain’s blood vessels is not simply a late consequence of Alzheimer’s disease; it is a biologically active process caused by APOE4 that may be reversible,” said Joel Blanchard, PhD, associate professor of neuroscience, and stem cell biology and regenerative medicine at Mount Sinai and a corresponding author on the study. Furthermore, “ through our experiments, we were able to block this protein buildup process, revealing possible new therapeutic treatment options and strategies for protecting the brain’s circulation in people at high genetic risk for Alzheimer’s disease,” said Braxton Schuldt, MD/PhD candidate in neuroscience and researcher in the Blanchard Laboratory at Mount Sinai. He is also the first author on the paper. 

For the Cell Stem Cell study, the Mount Sinai scientists and their collaborators elsewhere used miBrains to investigate how APOE4 promotes abnormal protein build up in diseases like Alzheimer’s and Parkinson’s. Derived from induced pluripotent stem cells, miBrains are three-dimensional human brain tissues developed by the Mount Sinai team to model key features of the human brain and its vascular network. These 3D tissues contain all the major cell types, including neurons, supporting glial cells, myelin-producing cells, and cells that form blood vessels. 

They also mimic the behavior of human brains carrying APOE4. Specifically, miBrains carrying APOE4 accumulate higher levels of abnormal alpha-synuclein, the protein commonly associated with Lewy body dementia and Parkinson’s disease. Experiments reported in the paper showed that APOE4 causes cholesterol to accumulate in astrocytes, and that this excess cholesterol impairs the astrocytes’ lysosomal waste-disposal system, reducing their ability to break down alpha-synuclein. The protein instead aggregates and spreads to neurons, leading to harmful protein deposits. The findings identify cholesterol metabolism in astrocytes and lysosomal function as promising therapeutic targets for Alzheimer’s and Parkinson’s disease.

“A key advance of our technology is that miBrains with predefined cellular compositions and disease-related factors can be cryopreserved,” said Louise Mesentier-Louro, PhD, assistant professor of neuroscience, and stem cell biology and regenerative medicine at Mount Sinai and first author of the study. “This capability improves reproducibility and scalability of complex disease modeling and supports more efficient drug development and validation.”

Da:

https://www.genengnews.com/topics/translational-medicine/apoe4-linked-to-potentially-reversible-mechanisms-of-brain-blood-vessel-damage-in-alzheimers/?_hsenc=p2ANqtz-_UOLjklVonxrcJXAwjb0DQmXwxkRPmLqXWMJQ7w0y9olMncI6Ax16tSTVCq98j9I9Y66bGgdy6TkS9AwUXtjcGD_ktjVreWjxIQgL14S5tkXUEhlU&_hsmi=440967978