Biology subjects

Grassi, C.

Publications and source records attributed to Grassi, C..

3 recordsLinked to original sources

bioRxiv2024

Recovery after human bone marrow mesenchymal stem cells (hBM-MSCs)-derived extracellular vesicles (EVs) treatment in post-MCAO rats requires handling associated with repeated behavioral testing.

Rehabilitation is the only current intervention that improves sensorimotor function in ischemic stroke patients, similar to task-specific intensive training in animal models of stroke. Bone marrow mesenchymal stem cells (BM-MSCs)-derived extracellular vesicles (EVs) are promising in restoring brain damage and function in stroke models. Additionally, the non-invasive intranasal route allows EVs to reach the brain and target specific ischemic regions. Yet unclear is how handling might enhance recovery or influence other therapies such as EVs after stroke. We used the transient middle cerebral artery occlusion (MCAO) model of stroke in rats to assess how intensive handling alone, in the form of sensorimotor behavioral tests, or in combination with an intranasal multidose or single dose of EVs restored neurological function and ischemic damage. Handled rats were exposed to a battery of sensorimotor tests, including the modified Neurological Severity Score (mNSS), beam balance, corner, grid walking, forelimb placement, and cylinder tests, together with Magnetic Resonance Imaging (MRI) at 2, 7, 14, 21, and 28 days post-stroke (dps). Handled MCAO rats were also exposed to an intranasal multidose of EVs (8 doses in total across four weeks, each dose containing 0.8 x 109 EVs in 120 {micro}l) or a single dose of EVs (2.4 x 109 EVs in 200 {micro}l) at 2 dps. Non-handled rats were evaluated only by mNSS and MRI at 2, 28, and 56 dps and were treated with a single intranasal dose of EVs. Our results showed that handling animals after MCAO is necessary for EVs to work and that a single cumulative dose of EVs further improves the neurological function recovered during handling without affecting ischemic damage. These results show the importance of rehabilitation in combination with other treatments and highlight how intensive behavioral testing might influence functional recovery after stroke, especially when other treatments are also given.

neuroscience↗

bioRxiv2022

Signal Peptide Peptidase-Like 2b affects APP cleavage and exhibits a biphasic Aβ-mediated expression in Alzheimer's disease.

Alzheimers disease (AD) is a multifactorial disorder driven by abnormal amyloid {beta}-peptide (A{beta}) levels. To identify new druggable pathways involved in the A{beta} cascade we here investigated the AD pathophysiological role of the presenilin-like intramembrane protease signal peptide peptidase-like 2b (SPPL2b). A{beta}42 induced a biphasic modulation of SPPL2b expression in human cell lines and ex vivo mouse brain slices. In addition, SPPL2b was elevated in AppNL-G-F knock-in AD mice as well as in human AD samples. Early high neuronal expression of SPPL2b was followed by a downregulation in late AD pathology in both AppNL-G-F mice and Braak stage V AD brains. Importantly, SPPL2b overexpression or its genetic deletion significantly increased or reduced APP cleavage and A{beta} production, respectively. Thus, our results strongly support the involvement of SPPL2b in AD pathology. The early A{beta}-induced SPPL2b upregulation may enhance A{beta} production in a vicious cycle further aggravating the A{beta} pathology suggesting SPPL2b as a potential anti-A{beta} drug target.

neuroscience↗

bioRxiv2021

A failure of β-amyloid physiological function due to genetic deletion of α7 nicotinic acetylcholine receptors induces an Alzheimer's disease-like pathology

The accumulation of amyloid-beta peptide (A{beta}) and the failure of cholinergic transmission are key players in Alzheimers disease (AD). However, in the healthy brain, A{beta} contributes to synaptic plasticity and memory acting through 7 subtype nicotinic acetylcholine receptors (7nAChRs). Here, we hypothesized that the 7nAChR deletion blocks A{beta} physiological function and promotes a compensatory increase in A{beta} levels that, in turn, triggers an AD-like pathology. To validate this hypothesis, we studied the age-dependent phenotype of 7 knock out mice. We found that 7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and A{beta} levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3{beta} at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and astrocytosis. Our findings suggest that 7nAChR malfunction might precede A{beta} and tau pathology, offering a different perspective to interpret the failure of anti-A{beta} therapies against AD and to find novel therapeutical approaches aimed at restoring 7nAChRs-mediated A{beta} function at the synapse.

neuroscience↗