Biology subjects

Garibotto, V.

Publications and source records attributed to Garibotto, V..

3 recordsLinked to original sources

bioRxiv2023

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Multiple lines of evidence point to peripheral immune alterations in bipolar disorder (BD) although the activity of brain immune mechanisms remain largely unexplored. To identify the cell type-specific immune alterations in the BD brain, we performed a proteomic and single nuclear transcriptomic analysis of postmortem cingulate cortex samples from BD and control subjects. Our results showed that genes associated to the genetic risk for BD are enriched in microglia and astrocytes. Transcriptomic alterations in microglia point to a reduced proinflammatory phenotype, associated to reduced resistance to oxidative stress and apoptosis, which was confirmed with immunohistochemical quantification of IBA1 density. Astrocytes show transcriptomic evidence of an imbalance of multiple metabolic pathways, extracellular matrix composition and downregulated immune signalling. These alterations are associated to ADCY2 and NCAN, two GWAS genes upregulated in astrocytes. Finally, cell-cell communication analysis prioritized upregulated SPP1-CD44 signalling to astrocytes as a potential regulator of the transcriptomic alterations in BD. Our results indicate that microglia and astrocytes are characterized by downregulated immune responses associated to a dysfunction of core mechanisms via which these cells contribute to brain homeostasis.

neuroscience↗

bioRxiv2022

Knockout of TSPO delays and reduces amyloid, Tau, astrocytosis and behavioral dysfunctions in Alzheimer's disease.

The 18kDa translocator protein (TSPO) is up-regulated in glial cells in neurodegenerative diseases. In Alzheimers disease (AD) animal models, TSPO is first overexpressed in astrocytes and then in microglia. However, the precise role of TSPO in the onset and progression of pathology and symptoms characteristic of the disease remains unknown. Here, we report that in the absence of TSPO in 3xTgAD mice the expected disease onset is significantly delayed and a reduction is seen in the hippocampal load of poorly and highly aggregated forms of Tau (-44% and -82%, respectively) and A{beta}42 (-25% and -95%, respectively), at 9 months of age. In addition, the astrocyte reactivity was decreased in 3xTgAD.TSPO-/- mice with a reduction in the morphologic complexity and the size of astrocytes in the dorso-dorsal hippocampus and the hilus. Functionally, the absence of TSPO ameliorated the cognitive consequences of adeno-associated virus-induced Tau over-expression in the hippocampus. This suggests that TSPO plays an important role in the active disease progression of AD. TSPO-inhibiting drugs thus merit further exploration as to their potential to reduce the rate of neurodegenerative disease progression.

pathology↗

bioRxiv2022

Fingerprinting of brain disease: Connectome identifiability in cognitive decline and neurodegeneration

In analogy to the friction ridges of a human finger, the functional connectivity patterns of the human brain can be used to identify a given individual from a population. In other words, functional connectivity patterns constitute a marker of human identity, or a brain fingerprint. Yet remarkably, very little is known about whether brain fingerprints are preserved in brain ageing and in the presence of cognitive decline due to Alzheimers disease (AD). Using fMRI data from two independent datasets of healthy and pathologically ageing subjects, here we show that individual functional connectivity profiles remain unique and highly heterogeneous across early and late stages of cognitive decline due to AD. Yet, the patterns of functional connectivity making subjects identifiable, change across health and disease, revealing a functional reconfiguration of the brain fingerprint. We observed a fingerprint change towards between-functional system connections when transitioning from healthy to dementia, and to lower-order cognitive functions in the earliest stages of the disease. These findings show that functional connectivity carries important individualised information to evaluate regional and network dysfunction in cognitive impairment and highlight the importance of switching the focus from group differences to individual variability when studying functional alterations in AD. The present data establish the foundation for clinical fingerprinting of brain diseases by showing that functional connectivity profiles maintain their uniqueness, yet go through functional reconfiguration, during cognitive decline. These results pave the way for a more personalised understanding of functional alterations during cognitive decline, moving towards brain fingerprinting in personalised medicine and treatment optimization during cognitive decline.

neuroscience↗