TY - JOUR
T1 - Distinct tau and alpha-synuclein molecular signatures in Alzheimer’s disease with and without Lewy bodies and Parkinson’s disease with dementia
AU - van der Gaag, Bram L.
AU - Deshayes, Natasja A. C.
AU - Breve, John J. P.
AU - Bol, John G. J. M.
AU - Jonker, Allert J.
AU - Hoozemans, Jeroen J. M.
AU - Courade, Jean-Philippe
AU - van de Berg, Wilma D. J.
N1 - Funding Information: This work was funded by Discoveric bio alpha ltd. JPC is an employee and stock owner of Discoveric bio alpha ltd. WvdB was financially supported by grants from Dutch Research Council (ZonMW 70-73305-98-106; 70-73305-98-102; 40-46000-98-101), Stichting Parkinson Fonds (Insula 2014–2019), Alzheimer association (AARF-18-566459), MJ Fox foundation (17253; 22468), Parkinson Association (2020-G01) and Health Holland. WvdB performed contract research for Roche Tissue Diagnostics, Crossbeta Sciences, Discoveric bio alpha LtD and received research consumables from Hoffmann-La Roche and Prothena. Publisher Copyright: © 2024, The Author(s).
PY - 2024/6/1
Y1 - 2024/6/1
N2 - Alpha-synuclein (aSyn) pathology is present in approximately 50% of Alzheimer’s disease (AD) cases at autopsy and might impact the age-of-onset and disease progression in AD. Here, we aimed to determine whether tau and aSyn profiles differ between AD cases with Lewy bodies (AD-LB), pure AD and Parkinson’s disease with dementia (PDD) cases using epitope-, post-translational modification- (PTM) and isoform-specific tau and aSyn antibody panels spanning from the N- to C-terminus. We included the middle temporal gyrus (MTG) and amygdala (AMY) of clinically diagnosed and pathologically confirmed cases and performed dot blotting, western blotting and immunohistochemistry combined with quantitative and morphological analyses. All investigated phospho-tau (pTau) species, except pT181, were upregulated in AD-LB and AD cases compared to PDD and control cases, but no significant differences were observed between AD-LB and AD subjects. In addition, tau antibodies targeting the proline-rich regions and C-terminus showed preferential binding to AD-LB and AD brain homogenates. Antibodies targeting C-terminal aSyn epitopes and pS129 aSyn showed stronger binding to AD-LB and PDD cases compared to AD and control cases. Two pTau species (pS198 and pS396) were specifically detected in the soluble protein fractions of AD-LB and AD subjects, indicative of early involvement of these PTMs in the multimerization process of tau. Other phospho-variants for both tau (pT212/S214, pT231 and pS422) and aSyn (pS129) were only detected in the insoluble protein fraction of AD-LB/AD and AD-LB/PDD cases, respectively. aSyn load was higher in the AMY of AD-LB cases compared to PDD cases, suggesting aggravated aSyn pathology under the presence of AD pathology, while tau load was similar between AD-LB and AD cases. Co-localization of pTau and aSyn could be observed within astrocytes of AD-LB cases within the MTG. These findings highlight a unique pathological signature for AD-LB cases compared to pure AD and PDD cases.
AB - Alpha-synuclein (aSyn) pathology is present in approximately 50% of Alzheimer’s disease (AD) cases at autopsy and might impact the age-of-onset and disease progression in AD. Here, we aimed to determine whether tau and aSyn profiles differ between AD cases with Lewy bodies (AD-LB), pure AD and Parkinson’s disease with dementia (PDD) cases using epitope-, post-translational modification- (PTM) and isoform-specific tau and aSyn antibody panels spanning from the N- to C-terminus. We included the middle temporal gyrus (MTG) and amygdala (AMY) of clinically diagnosed and pathologically confirmed cases and performed dot blotting, western blotting and immunohistochemistry combined with quantitative and morphological analyses. All investigated phospho-tau (pTau) species, except pT181, were upregulated in AD-LB and AD cases compared to PDD and control cases, but no significant differences were observed between AD-LB and AD subjects. In addition, tau antibodies targeting the proline-rich regions and C-terminus showed preferential binding to AD-LB and AD brain homogenates. Antibodies targeting C-terminal aSyn epitopes and pS129 aSyn showed stronger binding to AD-LB and PDD cases compared to AD and control cases. Two pTau species (pS198 and pS396) were specifically detected in the soluble protein fractions of AD-LB and AD subjects, indicative of early involvement of these PTMs in the multimerization process of tau. Other phospho-variants for both tau (pT212/S214, pT231 and pS422) and aSyn (pS129) were only detected in the insoluble protein fraction of AD-LB/AD and AD-LB/PDD cases, respectively. aSyn load was higher in the AMY of AD-LB cases compared to PDD cases, suggesting aggravated aSyn pathology under the presence of AD pathology, while tau load was similar between AD-LB and AD cases. Co-localization of pTau and aSyn could be observed within astrocytes of AD-LB cases within the MTG. These findings highlight a unique pathological signature for AD-LB cases compared to pure AD and PDD cases.
KW - Blotting
KW - Co-pathology
KW - Immunohistochemistry
KW - Post-translational modifications
UR - http://www.scopus.com/inward/record.url?scp=85181939962&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00401-023-02657-y
DO - https://doi.org/10.1007/s00401-023-02657-y
M3 - Article
C2 - 38198008
SN - 0001-6322
VL - 147
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 1
M1 - 14
ER -