Basic Science and Pathogenesis.

Background: Anti-amyloid-β (Aβ) immunotherapy trials have shown amyloid-related imaging abnormalities (ARIA) as the most common and serious adverse events linked to pathological changes in cerebral vasculature. Nevertheless, the mechanisms underlying how amyloid immunotherapy triggers vascular damage, increases vascular permeability, and results in microhemorrhages remains unclear. Notably, activation of perivascular macrophages and infiltration of peripheral immune cells have been implicated in regulating cerebrovascular damage.

Amyloid-β (Aβ) immunotherapy induced microhemorrhages are linked to vascular inflammation and cerebrovascular damage in a mouse model of Alzheimer's disease.

Background: Anti-amyloid-β (Aβ) immunotherapy trials have revealed amyloid-related imaging abnormalities (ARIA) as the most prevalent and serious adverse events linked to pathological changes in cerebral vasculature. Recent studies underscore the critical involvement of perivascular macrophages and the infiltration of peripheral immune cells in regulating cerebrovascular damage. Specifically, Aβ antibodies engaged at cerebral amyloid angiopathy (CAA) deposits trigger perivascular macrophage activation and the upregulation of genes associated with vascular permeability.

Up-Regulation of Astrocytic Fgfr4 Expression in Adult Mice after Spinal Cord Injury.

Spinal cord injury (SCI) leads to persistent neurological deficits without available curative treatment. After SCI astrocytes within the lesion vicinity become reactive, these undergo major morphological, and molecular transformations. Previously, we reported that following SCI, over 10% of resident astrocytes surrounding the lesion spontaneously transdifferentiate towards a neuronal phenotype.

Intrinsic regulation of axon regeneration after spinal cord injury: Recent advances and remaining challenges.

Spinal cord injury (SCI) is a disastrous event causing irreversible loss of both sensory and motor function. After SCI, both ascending dorsal column axons and descending corticospinal tract (CST) axons undergo rapid degeneration that is subsequently followed by slow axonal dieback and retraction bulb formation. Pre-clinical studies over the last two decades using genetic and, to a lesser extent, pharmacological approaches have identified several molecules that regulate intrinsic axon regeneration after SCI.

Co-targeting B-RAF and PTEN Enables Sensory Axons to Regenerate Across and Beyond the Spinal Cord Injury.

Primary sensory axons in adult mammals fail to regenerate after spinal cord injury (SCI), in part due to insufficient intrinsic growth potential. Robustly boosting their growth potential continues to be a challenge. Previously, we showed that constitutive activation of B-RAF (rapidly accelerated fibrosarcoma kinase) markedly promotes axon regeneration after dorsal root and optic nerve injuries.

Unlike Brief Inhibition of Microglia Proliferation after Spinal Cord Injury, Long-Term Treatment Does Not Improve Motor Recovery.

Microglia are major players in scar formation after an injury to the spinal cord. Microglia proliferation, differentiation, and survival are regulated by the colony-stimulating factor 1 (CSF1). Complete microglia elimination using CSF1 receptor (CSF1R) inhibitors worsens motor function recovery after spinal injury (SCI).

The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation.

Atr is a serine/threonine kinase, known to sense single-stranded DNA breaks and activate the DNA damage checkpoint by phosphorylating Chek1, which inhibits Cdc25, causing cell cycle arrest. This pathway has not been implicated in neuroregeneration. We show that in Drosophila sensory neurons removing Atr or Chek1, or overexpressing Cdc25 promotes regeneration, whereas Atr or Chek1 overexpression, or Cdc25 knockdown impedes regeneration.

Glial Metabolic Rewiring Promotes Axon Regeneration and Functional Recovery in the Central Nervous System.

Axons in the mature central nervous system (CNS) fail to regenerate after axotomy, partly due to the inhibitory environment constituted by reactive glial cells producing astrocytic scars, chondroitin sulfate proteoglycans, and myelin debris. We investigated this inhibitory milieu, showing that it is reversible and depends on glial metabolic status. We show that glia can be reprogrammed to promote morphological and functional regeneration after CNS injury in Drosophila via increased glycolysis.

Serotonergic mechanisms in spinal cord injury.

Spinal cord injury (SCI) is a tragic event causing irreversible losses of sensory, motor, and autonomic functions, that may also be associated with chronic neuropathic pain. Serotonin (5-HT) neurotransmission in the spinal cord is critical for modulating sensory, motor, and autonomic functions. Following SCI, 5-HT axons caudal to the lesion site degenerate, and the degree of axonal degeneration positively correlates with lesion severity.

CSF1R Inhibition Reduces Microglia Proliferation, Promotes Tissue Preservation and Improves Motor Recovery After Spinal Cord Injury.

Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by activation and proliferation of resident microglia as well as infiltrating peripheral monocyte-derived macrophages. Depending on the time post-lesion, positive and detrimental influences of microglia/macrophages on axonal regeneration had been reported after SCI, raising the issue whether their modulation may represent an attractive therapeutic strategy. Colony-stimulating factor 1 (CSF1) regulates microglia/macrophages proliferation, differentiation and survival thus, pharmacological treatments using CSF1 receptor (CSF1R) inhibitors had been used to ablate microglia.

C57BL/6 and Swiss Webster Mice Display Differences in Mobility, Gliosis, Microcavity Formation and Lesion Volume After Severe Spinal Cord Injury.

Spinal cord injuries (SCI) are neuropathologies causing enormous physical and emotional anguish as well as irreversibly disabilities with great socio/economic burdens to our society. The availability of multiple mouse strains is important for studying the underlying pathophysiological response after SCI. Although strain differences have been shown to directly affect spontaneous functional recovery following incomplete SCI, its influence after complete lesion of the spinal cord is unclear.

Longitudinal Magnetic Resonance Imaging Analysis and Histological Characterization after Spinal Cord Injury in Two Mouse Strains with Different Functional Recovery: Gliosis as a Key Factor.

Spinal cord injuries (SCI) are disastrous neuropathologies causing permanent disabilities. The availability of different strains of mice is valuable for studying the pathophysiological mechanisms involved in SCI. However, strain differences have a profound effect on spontaneous functional recovery after SCI.

A Novel Translational Model of Spinal Cord Injury in Nonhuman Primate.

Spinal cord injuries (SCI) lead to major disabilities affecting > 2.5 million people worldwide. Major shortcomings in clinical translation result from multiple factors, including species differences, development of moderately predictive animal models, and differences in methodologies between preclinical and clinical studies.

Microglia Responses in Acute and Chronic Neurological Diseases: What Microglia-Specific Transcriptomic Studies Taught (and did Not Teach) Us.

Over the last decade, microglia have been acknowledged to be key players in central nervous system (CNS) under both physiological and pathological conditions. They constantly survey the CNS environment and as immune cells, in pathological contexts, they provide the first host defense and orchestrate the immune response. It is well recognized that under pathological conditions microglia have both sequential and simultaneous, beneficial and detrimental effects.

A Combination of Diffusion MRI and Multiphoton to Study Microglia/Monocytes Alterations after Spinal Cord Injury.

Central nervous system (CNS) injury has been observed to lead to microglia activation and monocytes infiltration at the lesion site. diffusion magnetic resonance imaging (diffusion MRI or DWI) allows detailed examination of CNS tissues, and recent advances in clearing procedures allow detailed imaging of fluorescent-labeled cells at high resolution. No study has yet combined diffusion MRI and clearing procedures to establish a possible link between microglia/monocytes response and diffusion coefficient in the context of spinal cord injury (SCI).

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury.

Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site.

Spinal cord injury induces astroglial conversion towards neuronal lineage.

Background: Neurons have intrinsic capability to regenerate after lesion, though not spontaneously. Spinal cord injury (SCI) causes permanent neurological impairments partly due to formation of a glial scar that is composed of astrocytes and microglia. Astrocytes play both beneficial and detrimental roles on axonal re-growth, however, their precise role after SCI is currently under debate.

Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS.

Background: There is growing evidence that microglia are key players in the pathological process of amyotrophic lateral sclerosis (ALS). It is suggested that microglia have a dual role in motoneurone degeneration through the release of both neuroprotective and neurotoxic factors.

Results: To identify candidate genes that may be involved in ALS pathology we have analysed at early symptomatic age (P90), the molecular signature of microglia from the lumbar region of the spinal cord of hSOD1(G93A) mice, the most widely used animal model of ALS.

Correlation of in vivo and ex vivo (1)H-MRI with histology in two severities of mouse spinal cord injury.

Spinal cord injury (SCI) is a debilitating neuropathology with no effective treatment. Magnetic resonance imaging (MRI) technology is the only method used to assess the impact of an injury on the structure and function of the human spinal cord. Moreover, in pre-clinical SCI research, MRI is a non-invasive method with great translational potential since it provides relevant longitudinal assessment of anatomical and structural alterations induced by an injury.

The serotonergic system in ageing and Alzheimer's disease.

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression.