Biology subjects

Oliveira da Silva, M. I.

Publications and source records attributed to Oliveira da Silva, M. I..

3 recordsLinked to original sources

bioRxiv2025

Neuronal expression of S100B triggered by oligomeric Aβ peptide protects against cytoskeletal damage and synaptic loss

Alzheimers disease (AD) is a complex neurodegenerative disorder characterized by the intracellular deposition of Tau protein and extracellular deposition of amyloid-{beta} peptide (A{beta}). AD is also characterized by neuroinflammation and synapse loss, among others. The S100 family is a group of calcium-binding proteins with intra- and extracellular functions, that are important modulators of inflammatory responses. S100B, which is upregulated in AD patients and the most abundant member of this family, was shown to inhibit in vitro the aggregation and toxicity of A{beta}42, acting as a neuroprotective holdase-type chaperone. Although S100B is primarily produced by astrocytes, it is also expressed by various cells, including neurons. In this work, we investigated if S100B neuronal expression is triggered as a response to A{beta} toxic species, to provide protection during disease progression. We used the AD mouse model A{beta}PPswe/PS1A246E to show that neuronal S100B levels are significantly higher in 10-month-old animals, and cellular assays to demonstrate that A{beta} oligomers significantly increase S100B expression in SH-SY5Y cells, but not monomeric or fibrillar A{beta}. Using primary cultures of rat hippocampal neurons, we showed that S100B partially reverts A{beta}-induced cofilin-actin rods (synapse disruptors), and rescues the decrease in active synapses and post- (PSD-95) synaptic marker, imposed by A{beta} peptide. Altogether, these findings establish the neuroprotective activity of S100B in response to proteotoxic stress in cells, highlighting its chaperone function as a crucial factor in understanding proteostasis regulation in the diseased brain and identifying potential therapeutic targets.

neuroscience↗

bioRxiv2024

Rac1 inhibition prevents axonal cytoskeleton dysfunction in Transthyretin Amyloid Polyneuropathy

Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is characterized by the deposition of amyloidogenic TTR, particularly in dorsal root ganglia (DRG) and peripheral nerve axons, resulting in sensorimotor axonopathy with autonomic dysfunction. Here, we investigated cytoskeleton alterations in peripheral axons from an ATTRv-PN mouse model, the hTTRA97S knock-in mice. Proteomics of hTTRA97S sural nerves revealed dysregulation of actin-related proteins. hTTRA97S DRG neurons presented a defective actin distribution in growth cones along with a reduction in axonal actin trails, and an associated impairment in the pool of pre-synaptic vesicles. Microtubule dynamics and axonal transport abnormalities were also observed in mutant axons. Importantly, cytoskeletal defects in hTTRA97S neurons preceded axonal degeneration and were mediated by Rac1 hyperactivation in DRG neurites and sciatic nerves of pre-symptomatic mice. Rac1 inhibition rescued cytoskeleton alterations, preventing degeneration. Remarkably, in ATTRv-PN patients with late-onset disease, a variant in RACGAP1, encoding a Rac1 inactivator, supported the neuroprotective role of Rac1 inhibition. Our findings demonstrate that cytoskeletal defects precede axonal degeneration in ATTRv-PN and highlight Rac1 as a promising therapeutic target.

neuroscience↗

bioRxiv2021

Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy

Cognitive dysfunction and dementia are presently recognized as major complications in -synucleinopathies, namely in Dementia with Lewy Bodies (DLB) and Parkinsons disease with dementia (PDD). In these disorders, -Synuclein (Syn) accumulation affects severely the hippocampus by inducing synaptic dysfunction which culminates in cognitive impairment. To characterize the mechanisms underlying Syn-induced neuronal dysfunction we analysed the effect of overexpression or extracellular administration of Syn on hippocampal neurons. We observed that Syn induces the dysregulation of the actin-binding protein cofilin and its assembly into rod structures in a mechanism mediated by the cellular prion protein (PrPC). Moreover, we unraveled cofilin pathology as mediator of Syn-induced dendritic spine impairment in hippocampal neurons. Importantly, in a synucleinopathy mouse model with cognitive impairment we validated cofilin dysregulation and synaptic dysfunction at the same age when cognitive deficits were observed. Our data supports cofilin as a novel player on hippocampal synaptic dysfunction triggered by Syn on Lewy Body dementias.

neuroscience↗