Lowering levels of reelin in entorhinal cortex layer II-neurons results in lowered levels of intracellular amyloid-β
Kobro-Flatmoen, Asgeir ; Battistin, Claudia ; Nair, Rajeevkumar Raveendran ; Bjorkli, Christiana ; Skender, Belma ; Kentros, Cliff ; Gouras, Gunnar LU
and Witter, Menno P
(2023)
In Brain Communications
5(2).
p.1-15
- Abstract
Projection neurons in the anteriolateral part of entorhinal cortex layer II are the predominant cortical site for hyper-phosphorylation of tau and formation of neurofibrillary tangles in prodromal Alzheimer's disease. A majority of layer II projection neurons in anteriolateral entorhinal cortex are unique among cortical excitatory neurons by expressing the protein reelin. In prodromal Alzheimer's disease, these reelin-expressing neurons are prone to accumulate intracellular amyloid-β, which is mimicked in a rat model that replicates the spatio-temporal cascade of the disease. Two important findings in relation to this are that reelin-signalling downregulates tau phosphorylation, and that oligomeric amyloid-β interferes with... (More)
Projection neurons in the anteriolateral part of entorhinal cortex layer II are the predominant cortical site for hyper-phosphorylation of tau and formation of neurofibrillary tangles in prodromal Alzheimer's disease. A majority of layer II projection neurons in anteriolateral entorhinal cortex are unique among cortical excitatory neurons by expressing the protein reelin. In prodromal Alzheimer's disease, these reelin-expressing neurons are prone to accumulate intracellular amyloid-β, which is mimicked in a rat model that replicates the spatio-temporal cascade of the disease. Two important findings in relation to this are that reelin-signalling downregulates tau phosphorylation, and that oligomeric amyloid-β interferes with reelin-signalling. Taking advantage of this rat model, we used proximity ligation assay to assess whether reelin and intracellular amyloid-β directly interact during early, pre-plaque stages in anteriolateral entorhinal cortex layer II reelin-expressing neurons. We next made a viral vector delivering micro-RNA against reelin, along with a control vector, and infected reelin-expressing anteriolateral entorhinal cortex layer II-neurons to test whether reelin levels affect levels of intracellular amyloid-β and/or amyloid precursor protein. We analysed 25.548 neurons from 24 animals, which results in three important findings. First, in reelin-expressing anteriolateral entorhinal cortex layer II-neurons, reelin and intracellular amyloid-β engage in a direct protein-protein interaction. Second, injecting micro-RNA against reelin lowers reelin levels in these neurons, amounting to an effect size of 1.3-4.5 (Bayesian estimation of Cohen's
(Less)
d effect size, 95% credible interval). This causes a concomitant reduction of intracellular amyloid-β ranging across three levels of aggregation, including a reduction of Aβ42 monomers/dimers amounting to an effect size of 0.5-3.1, a reduction of Aβ prefibrils amounting to an effect size of 1.1-3.5 and a reduction of protofibrils amounting to an effect size of 0.05-2.1. Analysing these data using Bayesian estimation of mutual information furthermore reveals that levels of amyloid-β are dependent on levels of reelin. Third, the reduction of intracellular amyloid-β occurs without any substantial associated changes in levels of amyloid precursor protein. We conclude that reelin and amyloid-β directly interact at the intracellular level in the uniquely reelin-expressing projection neurons in anteriolateral entorhinal cortex layer II, where levels of amyloid-β are dependent on levels of reelin. Since amyloid-β is known to impair reelin-signalling causing upregulated phosphorylation of tau, our findings are likely relevant to the vulnerability for neurofibrillary tangle-formation of this entorhinal neuronal population.
- author
- Kobro-Flatmoen, Asgeir
; Battistin, Claudia
; Nair, Rajeevkumar Raveendran
; Bjorkli, Christiana
; Skender, Belma
; Kentros, Cliff
; Gouras, Gunnar
LU
and Witter, Menno P
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Brain Communications
- volume
- 5
- issue
- 2
- article number
- fcad115
- pages
- 1 - 15
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85160045607
- pmid:37091586
- ISSN
- 2632-1297
- DOI
- 10.1093/braincomms/fcad115
- language
- English
- LU publication?
- yes
- additional info
- © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.
- id
- 55bb2ae8-1a7a-4fe7-9f21-b7dc8d0bf30d
- date added to LUP
- 2023-05-15 17:14:46
- date last changed
- 2024-06-29 04:06:04
@article{55bb2ae8-1a7a-4fe7-9f21-b7dc8d0bf30d,
abstract = {{<p>Projection neurons in the anteriolateral part of entorhinal cortex layer II are the predominant cortical site for hyper-phosphorylation of tau and formation of neurofibrillary tangles in prodromal Alzheimer's disease. A majority of layer II projection neurons in anteriolateral entorhinal cortex are unique among cortical excitatory neurons by expressing the protein reelin. In prodromal Alzheimer's disease, these reelin-expressing neurons are prone to accumulate intracellular amyloid-β, which is mimicked in a rat model that replicates the spatio-temporal cascade of the disease. Two important findings in relation to this are that reelin-signalling downregulates tau phosphorylation, and that oligomeric amyloid-β interferes with reelin-signalling. Taking advantage of this rat model, we used proximity ligation assay to assess whether reelin and intracellular amyloid-β directly interact during early, pre-plaque stages in anteriolateral entorhinal cortex layer II reelin-expressing neurons. We next made a viral vector delivering micro-RNA against reelin, along with a control vector, and infected reelin-expressing anteriolateral entorhinal cortex layer II-neurons to test whether reelin levels affect levels of intracellular amyloid-β and/or amyloid precursor protein. We analysed 25.548 neurons from 24 animals, which results in three important findings. First, in reelin-expressing anteriolateral entorhinal cortex layer II-neurons, reelin and intracellular amyloid-β engage in a direct protein-protein interaction. Second, injecting micro-RNA against reelin lowers reelin levels in these neurons, amounting to an effect size of 1.3-4.5 (Bayesian estimation of Cohen's<br>
d effect size, 95% credible interval). This causes a concomitant reduction of intracellular amyloid-β ranging across three levels of aggregation, including a reduction of Aβ42 monomers/dimers amounting to an effect size of 0.5-3.1, a reduction of Aβ prefibrils amounting to an effect size of 1.1-3.5 and a reduction of protofibrils amounting to an effect size of 0.05-2.1. Analysing these data using Bayesian estimation of mutual information furthermore reveals that levels of amyloid-β are dependent on levels of reelin. Third, the reduction of intracellular amyloid-β occurs without any substantial associated changes in levels of amyloid precursor protein. We conclude that reelin and amyloid-β directly interact at the intracellular level in the uniquely reelin-expressing projection neurons in anteriolateral entorhinal cortex layer II, where levels of amyloid-β are dependent on levels of reelin. Since amyloid-β is known to impair reelin-signalling causing upregulated phosphorylation of tau, our findings are likely relevant to the vulnerability for neurofibrillary tangle-formation of this entorhinal neuronal population.<br>
</p>}},
author = {{Kobro-Flatmoen, Asgeir and Battistin, Claudia and Nair, Rajeevkumar Raveendran and Bjorkli, Christiana and Skender, Belma and Kentros, Cliff and Gouras, Gunnar and Witter, Menno P}},
issn = {{2632-1297}},
language = {{eng}},
number = {{2}},
pages = {{1--15}},
publisher = {{Oxford University Press}},
series = {{Brain Communications}},
title = {{Lowering levels of reelin in entorhinal cortex layer II-neurons results in lowered levels of intracellular amyloid-β}},
url = {{http://dx.doi.org/10.1093/braincomms/fcad115}},
doi = {{10.1093/braincomms/fcad115}},
volume = {{5}},
year = {{2023}},
}