Transformation of non-neuritic into neuritic plaques during AD progression drives cortical spread of tau pathology via regenerative failure.
Alzheimer’s disease
Dystrophic neurites
Neuritic plaque
Regenerative failure
Spatial transcriptomics
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
01 12 2023
01 12 2023
Historique:
received:
08
11
2023
accepted:
10
11
2023
medline:
4
12
2023
pubmed:
1
12
2023
entrez:
1
12
2023
Statut:
epublish
Résumé
Extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein in form of neurofibrillary tangles (NFT) are pathological hallmarks of Alzheimer's disease (AD). The exact mechanism how these two protein aggregates interact in AD is still a matter of debate. Neuritic plaques (NP), a subset of Aβ plaques containing dystrophic neurites (DN), are suggested to be unique to AD and might play a role in the interaction of Aβ and tau. Quantifying NP and non-NP in postmortem brain specimens from patients with increasing severity of AD neuropathological changes (ADNC), we demonstrate that the total number of Aβ plaques and NP increase, while the number of non-NP stagnates. Furthermore, investigating the correlation between NP and NFT, we identified unexpected brain region-specific differences when comparing cases with increasingly more severe ADNC. In neocortical regions NFT counts increase in parallel with NP counts during the progression of ADNC, while this correlation is not observed in hippocampus. These data support the notion that non-NP are transformed into NP during the progression of ADNC and indicate that NP might drive cortical NFT formation. Next, using spatial transcriptomics, we analyzed the gene expression profile of the microenvironment around non-NP and NP. We identified an upregulation of neuronal systems and Ca-dependent event pathways around NP compared to non-NP. We speculate that the upregulation of these transcripts may hint at a compensatory mechanism underlying NP formation. Our studies suggest that the transformation of non-NP to NP is a key event in ADNC progression and points to regenerative failure as a potential driving force of this process.
Identifiants
pubmed: 38037144
doi: 10.1186/s40478-023-01688-6
pii: 10.1186/s40478-023-01688-6
pmc: PMC10691154
doi:
Substances chimiques
tau Proteins
0
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
190Subventions
Organisme : NIA NIH HHS
ID : P50 AG047266
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG074569
Pays : United States
Organisme : NIA NIH HHS
ID : RF1AG074569
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG047266
Pays : United States
Informations de copyright
© 2023. The Author(s).
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