The AppNL‐G‐F/MAPT mouse model of Alzheimer’s Disease demonstrates increased levels of ptau217 in CSF, changes that correlate with increased cerebral p‐tau depositions
Year: 2023
Type: article
Abstract: Background Cerebrospinal fluid (CSF) biomarkers reflecting the neuropathological hallmarks of Alzheimer’s disease (AD) have during the two last decades been developed and are commonly used to diagnose patients with AD patients. Previous studies have shown that CSF p‐tau217 particularly well can separate AD patients from healthy controls and that CSF levels of ptau217 correlate significantly with the amyloid burden and tau pathology in the brain (determined by PET). However, more studies are needed to fully understand the temporal relationship between CSF p‐tau217 changes and the accumulation tau in the brain. In this current study, we aim to investigate these temporal associations by the use of a novel knock‐in mouse model, AppNL‐G‐F expressing all six isoforms of human MAPT. Method Cerebrospinal fluid (CSF) and brain tissue will be collected from 3‐22 months old AppNL‐G‐F /MAPT and MAPT knock‐in mice. A pilot study of a subset of mice at different ages has been performed where levels of CSF ptau217 were analyzed using Mesoscale Discovery developed by Eli Lilly and Company. Mouse brain sections were immunostained against Aß and ptau181/217/231 to determine the cerebral p‐tau distribution. Result In CSF from our AppNL‐G‐F /MAPT double knock‐in (dKi) mouse model, we found age‐related increases in ptau217 levels compared to MAPT Ki mice. These changes in CSF ptau217 were associated with an increase of cerebral accumulation of p‐tau positive inclusions in the cortex and hippocampus of these mice. Additionally, we also found temporal differences in co‐localization between Aß plaques and the investigated phosphorylation sites of tau. Conclusion Our preliminary results from the AppNL‐G‐F/MAPT double knock‐in model, show early alterations in CSF ptau217 levels, changes that correlate in time with cerebral p‐tau positive accumulation as well as formation of Aß plaques. These findings indicate that alterations in CSF and cerebral p‐tau occurs early in the disease, when Aß pathology is widespread but no tau tangles are present. Furthermore, our preliminary data suggest temporal differences in phosphorylation sites of tau associated with Aß pathology. Additional CSF analysis and immunostainings will be performed before the AAIC conference.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.079598
Institution: Lund University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4390199114