Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes.
Animals
Astrocytes
/ metabolism
Amyloid beta-Protein Precursor
/ genetics
Mice
Mice, Transgenic
Alzheimer Disease
/ metabolism
Transcriptome
Axon Initial Segment
/ metabolism
Coculture Techniques
Ankyrins
/ metabolism
Tretinoin
/ pharmacology
Neurons
/ metabolism
Disease Models, Animal
Axons
/ metabolism
Mice, Inbred C57BL
Presenilin-1
/ genetics
Receptors, Purinergic P2X7
/ metabolism
Cells, Cultured
Aldehyde Dehydrogenase 1 Family
/ metabolism
Nerve Tissue Proteins
/ metabolism
Retinal Dehydrogenase
/ metabolism
ADNP
AnkyrinG
Astrocytes
Axon initial segment
Neurodegeneration
P2X7
Retinoic acid
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
01 Nov 2024
01 Nov 2024
Historique:
received:
10
10
2023
accepted:
21
10
2024
revised:
20
09
2024
medline:
1
11
2024
pubmed:
1
11
2024
entrez:
1
11
2024
Statut:
epublish
Résumé
Alzheimer´s disease (AD) is characterized by neuronal function loss and degeneration. The integrity of the axon initial segment (AIS) is essential to maintain neuronal function and output. AIS alterations are detected in human post-mortem AD brains and mice models, as well as, neurodevelopmental and mental disorders. However, the mechanisms leading to AIS deregulation in AD and the extrinsic glial origin are elusive. We studied early postnatal differences in AIS cellular/molecular mechanisms in wild-type or APP/PS1 mice and combined neuron-astrocyte co-cultures. We observed AIS integrity alterations, reduced ankyrinG expression and shortening, in APP/PS1 mice from P21 and loss of AIS integrity at 21 DIV in wild-type and APP/PS1 neurons in the presence of APP/PS1 astrocytes. AnkyrinG decrease is due to mRNAs and protein reduction of retinoic acid synthesis enzymes Rdh1 and Aldh1b1, as well as ADNP (Activity-dependent neuroprotective protein) in APP/PS1 astrocytes. This effect was mimicked by wild-type astrocytes expressing ADNP shRNA. In the presence of APP/PS1 astrocytes, wild-type neurons AIS is recovered by inhibition of retinoic acid degradation, and Adnp-derived NAP peptide (NAPVSIPQ) addition or P2X7 receptor inhibition, both regulated by retinoic acid levels. Moreover, P2X7 inhibitor treatment for 2 months impaired AIS disruption in APP/PS1 mice. Our findings extend current knowledge on AIS regulation, providing data to support the role of astrocytes in early postnatal AIS modulation. In conclusion, AD onset may be related to very early glial cell alterations that induce AIS and neuronal function changes, opening new therapeutic approaches to detect and avoid neuronal function loss.
Identifiants
pubmed: 39485512
doi: 10.1007/s00018-024-05485-9
pii: 10.1007/s00018-024-05485-9
doi:
Substances chimiques
Amyloid beta-Protein Precursor
0
Ankyrins
0
Tretinoin
5688UTC01R
Presenilin-1
0
Receptors, Purinergic P2X7
0
Ank3 protein, mouse
0
Aldehyde Dehydrogenase 1 Family
EC 1.2.1
Nerve Tissue Proteins
0
Retinal Dehydrogenase
EC 1.2.1.36
P2rx7 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
444Subventions
Organisme : CIBERNED (CIBER-ISCIII)
ID : PI2016/01
Organisme : CIBERNED (CIBER-ISCIII)
ID : PI2016/01
Organisme : Agencia Estatal de Investigación
ID : PID2021-123140NB-I00
Organisme : Agencia Estatal de Investigación
ID : PID2021-124801NB-I00
Informations de copyright
© 2024. The Author(s).
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