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Preventive cognitive protection based on AAV9 overexpression of IGF1 in hippocampal astrocytes

Peralta, Facundo ; Escobedo, Ana Abril Vidal ; Hanotte, Juliette López ; Avallone, Martino LU ; Björklund, Tomas LU ; Reggiani, Paula Cecilia and Pardo, Joaquín LU (2024) In Neurobiology of Disease 200.
Abstract

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. We overexpressed IGF1 and the reporter TdTomato (TOM) in hippocampal astrocytes with bicistronic Adeno-Associated Virus (AAV) harboring the Glial Fibrillary Acidic Protein (GFAP) promoter and afterwards induced neurodegeneration by the intracerebroventricular (ICV) injection of streptozotocin (STZ), a rat model of behavioral impairment, neuroinflammation and shortening of hippocampal astrocytes. We achieved a... (More)

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. We overexpressed IGF1 and the reporter TdTomato (TOM) in hippocampal astrocytes with bicistronic Adeno-Associated Virus (AAV) harboring the Glial Fibrillary Acidic Protein (GFAP) promoter and afterwards induced neurodegeneration by the intracerebroventricular (ICV) injection of streptozotocin (STZ), a rat model of behavioral impairment, neuroinflammation and shortening of hippocampal astrocytes. We achieved a thorough transgene expression along the hippocampus with a single viral injection. Although species typical behavior was impaired, memory deficit was prevented by IGF1. STZ prompted astrocyte shortening, albeit the length of these cells in animals injected with GFP and IGF1 vectors did not statistically differ from the other groups. In STZ control animals, hippocampal microglial reactive cells increased dramatically, but this was alleviated in IGF1 rats. We conclude that overexpression of IGF1 in astrocytes prevents neurodegeneration onset. Hence, individuals with early neurotrophic exhaustion would be vulnerable to age-related neurodegeneration.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AAV9, Astrocytes, Gene therapy, Hippocampus, IGF1, Neurodegeneration
in
Neurobiology of Disease
volume
200
article number
106612
publisher
Elsevier
external identifiers
  • scopus:85199282523
  • pmid:39032798
ISSN
0969-9961
DOI
10.1016/j.nbd.2024.106612
language
English
LU publication?
yes
id
cf1c0b43-57f8-43f0-a2b5-f4b5e8626c71
date added to LUP
2024-09-02 15:03:24
date last changed
2024-09-16 16:23:34
@article{cf1c0b43-57f8-43f0-a2b5-f4b5e8626c71,
  abstract     = {{<p>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. We overexpressed IGF1 and the reporter TdTomato (TOM) in hippocampal astrocytes with bicistronic Adeno-Associated Virus (AAV) harboring the Glial Fibrillary Acidic Protein (GFAP) promoter and afterwards induced neurodegeneration by the intracerebroventricular (ICV) injection of streptozotocin (STZ), a rat model of behavioral impairment, neuroinflammation and shortening of hippocampal astrocytes. We achieved a thorough transgene expression along the hippocampus with a single viral injection. Although species typical behavior was impaired, memory deficit was prevented by IGF1. STZ prompted astrocyte shortening, albeit the length of these cells in animals injected with GFP and IGF1 vectors did not statistically differ from the other groups. In STZ control animals, hippocampal microglial reactive cells increased dramatically, but this was alleviated in IGF1 rats. We conclude that overexpression of IGF1 in astrocytes prevents neurodegeneration onset. Hence, individuals with early neurotrophic exhaustion would be vulnerable to age-related neurodegeneration.</p>}},
  author       = {{Peralta, Facundo and Escobedo, Ana Abril Vidal and Hanotte, Juliette López and Avallone, Martino and Björklund, Tomas and Reggiani, Paula Cecilia and Pardo, Joaquín}},
  issn         = {{0969-9961}},
  keywords     = {{AAV9; Astrocytes; Gene therapy; Hippocampus; IGF1; Neurodegeneration}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Neurobiology of Disease}},
  title        = {{Preventive cognitive protection based on AAV9 overexpression of IGF1 in hippocampal astrocytes}},
  url          = {{http://dx.doi.org/10.1016/j.nbd.2024.106612}},
  doi          = {{10.1016/j.nbd.2024.106612}},
  volume       = {{200}},
  year         = {{2024}},
}