Background: Sporadic Alzheimer's disease (sAD) is the most common form of dementia, characterized by a progressive decline in cognitive function and, cortical and hippocampal atrophy. Our objective is to develop neuroprotective therapies that promote the homeostatic and modulatory properties of astrocytes, and enhance their protective functions. Glial-derived neurotrophic factor (GDNF) has emerged as a promising factor for its ability to promote neuronal survival and function. However, the therapeutic potential of GDNF in AD remains uncertain. Consequently, we explored it in the sAD model induced by intracerebroventricular (icv) streptozotocin (STZ) in rats.
Method: We produced serotype 9 bicistronic adeno-associated viruses (AAV), expressing GDNF and GFP (control), driven by the gfaABC1D promoter, targeting astrocytes expressing glial fibrillary acidic protein (GFAP). AAVs were characterized using RT-qPCR and immunohistochemistry (IHC). For therapeutic approach, young male rats were divided into 4 groups: SHAM, STZ, GFP, and GDNF. On Experimental Day (ED) -28, animals received bilateral intrahippocampal injections of artificial cerebrospinal fluid (aCSF) (SHAM and STZ groups) or AAV-GFP/GDNF (GFP and GDNF groups). On ED 0, animals received bilateral icv injections of aCSF (SHAM group) or STZ (3mg/kg) (STZ, GFP, and GDNF groups). Between ED +17/+26, behavioral tests were conducted to evaluate species-typical behavior, object recognition memory, and spatial memory.
Result: AAV-GDNF and AAV-GFP were generated, and the overexpression of transgenes was confirmed by RT-qPCR and IHC. In the therapeutic approach, animals belonging to STZ and GFP groups showed significant deterioration in all assessed behaviors. GDNF overexpression prevented cognitive impairment in treated animals, as they showed no significant differences compared to the SHAM group in the analysed parameters. Additionally, AAV-GDNF treatment promoted an increase in branching and length of processes in the analysed astrocytes CONCLUSION: We investigated an innovative therapeutic method specifically focused on hippocampal astrocytes. This allowed us to overexpress GDNF, generating protective actions that mitigated behavioral and cognitive alterations in our sAD animals. Furthermore, by acting on the brain's astrocyte population, promoting an increase in their complexity, we could potentially have a positive effect on maintaining cerebral homeostasis.
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http://dx.doi.org/10.1002/alz.089831 | DOI Listing |
Alzheimers Dement
December 2024
National Council of Scientific and Technical Research (CONICET/UNLP), La Plata, Argentina.
Background: Sporadic Alzheimer's disease (sAD) is the most common form of dementia, characterized by a progressive decline in cognitive function and, cortical and hippocampal atrophy. Our objective is to develop neuroprotective therapies that promote the homeostatic and modulatory properties of astrocytes, and enhance their protective functions. Glial-derived neurotrophic factor (GDNF) has emerged as a promising factor for its ability to promote neuronal survival and function.
View Article and Find Full Text PDFMol Nutr Food Res
December 2024
The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of, Education, Guizhou Provincial Engineering Research Center of Ecological Food Innovation, Collaborative Innovation Center for Prevention and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, School of Public Health, Guizhou Medical University, Guiyang, 561113, China.
Scope: Grifola frondosa polysaccharide (GFP) has a positive effect in regulating type 2 diabetes mellitus (T2DM), but the understanding of its regulatory mechanism is still limited. Accumulating evidence suggests that hepatic inflammation is crucial in the onset and progression of insulin resistance (IR) and T2DM. However, the question of whether GFP can modulate T2DM via regulating hepatic inflammation and the underlying mechanism has not yet been reported.
View Article and Find Full Text PDFNeurobiol Dis
October 2024
Instituto de Investigaciones Bioquímicas de La Plata "Profesor Doctor Rodolfo R. Brenner". Facultad de Ciencias Médicas. Universidad Nacional de La Plata. Buenos Aires, Argentina; Molecular Neuromodulation, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. Electronic address:
Astrocytes play key roles in the brain. When astrocyte support fails, neurological disorders follow, resulting in disrupted synaptic communication, neuronal degeneration, and cell death. We posit that astrocytes overexpressing neurotrophic factors, such as Insulin Like Growth Factor 1 (IGF1), prevent the onset of neurodegeneration.
View Article and Find Full Text PDFSci China Life Sci
March 2024
Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively.
View Article and Find Full Text PDFHeliyon
May 2023
Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Background: miR-96-5p is a highly expressed microRNA in the retina of subjects with diabetes. The INS/AKT/GLUT4 signaling axis is the main cell signaling pathway of glucose uptake in cells. Here, we investigated the role of miR-96-5p in this signaling pathway.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!