Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ genetics
Amyloid beta-Protein Precursor
/ genetics
Animals
Brain
/ metabolism
Disease Models, Animal
Female
Gene Expression Profiling
/ methods
Gene Ontology
Gene Regulatory Networks
Humans
Male
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Neuronal Plasticity
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 04 2021
23 04 2021
Historique:
received:
10
10
2018
accepted:
15
03
2021
entrez:
24
4
2021
pubmed:
25
4
2021
medline:
11
5
2021
Statut:
epublish
Résumé
The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.
Identifiants
pubmed: 33893290
doi: 10.1038/s41467-021-22624-z
pii: 10.1038/s41467-021-22624-z
pmc: PMC8065162
doi:
Substances chimiques
Amyloid beta-Peptides
0
Amyloid beta-Protein Precursor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2421Subventions
Organisme : NINDS NIH HHS
ID : R01 NS083801
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG056768
Pays : United States
Organisme : NIA NIH HHS
ID : U54 AG054349
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA062203
Pays : United States
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