Alzheimer's disease (AD) is a global epidemic, affecting millions of people worldwide, and its prevalence is expected to increase dramatically in the coming decades. The pathological hallmarks of AD, considered critical for understanding its development and progression, primarily involve the accumulation of amyloid-b extracellular plaques and intraneuronal formation of neurofibrillary tangles (NFT). These neuropathological changes are associated with synaptic and neuronal degeneration, impacting regions crucial for cognitive function, such as the neocortex and hippocampus. Furthermore, a substantial body of literature supports the pivotal role of neuroinflammation in AD. Microglia, as sentinel immune cells in the CNS, play a critical role in responding to the buildup of amyloid-b plaques. A noteworthy shift in AD research involves the recognition of peripheral immune cells infiltrating the brain parenchyma. Of particular interest is the infiltration of neutrophils from the bloodstream into the brain parenchyma. The interplay between microglia and neutrophils in the CNS has raised numerous questions. This study aimed to unravel the mechanisms and progression of AD by employing network-based approaches to analyze the spatial organization and morphological changes in microglial cells and amyloid-b plaques in 5xFAD mice, a transgenic mouse model of AD and the association of the aforementioned changes with neutrophil infiltration in human AD patients. Our work began by focusing on microglial cell morphology in 5xFAD mice which revealed a significant reduction in the cellular area and volume of microglial cells as AD advanced. This was accompanied by somatic swelling in activated microglia, indicating their role in the release of pro-inflammatory cytokines. Three-dimensional imaging demonstrated a shift from a ramified to a hypertrophic state with shorter processes and reduced branching complexity, confirming the activation of microglial cells during AD progression. In addition, a network-based approach that used the spatial localization of microglial cells and amyloid-b suggested interactions between these components in the affected mouse AD brains. Machine learning models were employed to predict disease progression using network analysis based on the spatial distribution between microglia and amyloid deposits and the results uncover that these significant microglial changes correspond to the disease's stage. Our study was next extended to human AD patients, in which we observed that the majority of microglia exhibited a dystrophic morphology, compared to control cases, which predominantly showed ramified cells. Comparative analysis showed a significant reduction in ramified and activated microglia in control samples, with a significant increase in dystrophic microglia in AD- derived samples. Furthermore, an increased accumulation of neutrophils in the brain parenchyma of the same AD patients was observed, suggesting a correlation between neutrophil infiltration and microglia activation. Indeed, in vitro experiments confirmed that neutrophils derived from AD mice can activate microglial cells, inducing an increase in the intracellular calcium release. Collectively, our data point to a pathological role for the interplay between microglia cells, neutrophils, and amyloid deposition and underscores the importance of understanding the spatial organization and interactions between different cellular and neuropathological components in AD for advancing our knowledge of disease pathology and developing new effective treatments.

Reconstruction and analysis of interaction networks between myeloid immune cells and amyloid-beta deposits in alzheimer’s disease

Suli Aferdita
2024-01-01

Abstract

Alzheimer's disease (AD) is a global epidemic, affecting millions of people worldwide, and its prevalence is expected to increase dramatically in the coming decades. The pathological hallmarks of AD, considered critical for understanding its development and progression, primarily involve the accumulation of amyloid-b extracellular plaques and intraneuronal formation of neurofibrillary tangles (NFT). These neuropathological changes are associated with synaptic and neuronal degeneration, impacting regions crucial for cognitive function, such as the neocortex and hippocampus. Furthermore, a substantial body of literature supports the pivotal role of neuroinflammation in AD. Microglia, as sentinel immune cells in the CNS, play a critical role in responding to the buildup of amyloid-b plaques. A noteworthy shift in AD research involves the recognition of peripheral immune cells infiltrating the brain parenchyma. Of particular interest is the infiltration of neutrophils from the bloodstream into the brain parenchyma. The interplay between microglia and neutrophils in the CNS has raised numerous questions. This study aimed to unravel the mechanisms and progression of AD by employing network-based approaches to analyze the spatial organization and morphological changes in microglial cells and amyloid-b plaques in 5xFAD mice, a transgenic mouse model of AD and the association of the aforementioned changes with neutrophil infiltration in human AD patients. Our work began by focusing on microglial cell morphology in 5xFAD mice which revealed a significant reduction in the cellular area and volume of microglial cells as AD advanced. This was accompanied by somatic swelling in activated microglia, indicating their role in the release of pro-inflammatory cytokines. Three-dimensional imaging demonstrated a shift from a ramified to a hypertrophic state with shorter processes and reduced branching complexity, confirming the activation of microglial cells during AD progression. In addition, a network-based approach that used the spatial localization of microglial cells and amyloid-b suggested interactions between these components in the affected mouse AD brains. Machine learning models were employed to predict disease progression using network analysis based on the spatial distribution between microglia and amyloid deposits and the results uncover that these significant microglial changes correspond to the disease's stage. Our study was next extended to human AD patients, in which we observed that the majority of microglia exhibited a dystrophic morphology, compared to control cases, which predominantly showed ramified cells. Comparative analysis showed a significant reduction in ramified and activated microglia in control samples, with a significant increase in dystrophic microglia in AD- derived samples. Furthermore, an increased accumulation of neutrophils in the brain parenchyma of the same AD patients was observed, suggesting a correlation between neutrophil infiltration and microglia activation. Indeed, in vitro experiments confirmed that neutrophils derived from AD mice can activate microglial cells, inducing an increase in the intracellular calcium release. Collectively, our data point to a pathological role for the interplay between microglia cells, neutrophils, and amyloid deposition and underscores the importance of understanding the spatial organization and interactions between different cellular and neuropathological components in AD for advancing our knowledge of disease pathology and developing new effective treatments.
2024
Alzheimer's disease, microglia, neutrophils, Amyloid beta deposition, spatial organization
File in questo prodotto:
File Dimensione Formato  
Thesis Aferdita Suli final version PDFA OK.pdf

embargo fino al 31/07/2035

Tipologia: Tesi di dottorato
Licenza: Copyright dell'editore
Dimensione 15.85 MB
Formato Adobe PDF
15.85 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/1131408
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact