The deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological
hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively.
However, there is accumulative evidence that both proteins are not exclusive for their clinical entity
but instead co-exist and interact with each other. Here, we investigated the presence of a newly
identified, pyroglutamate79-modified α-synuclein variant (pGlu79-aSyn)—along with the enzyme
matrix metalloproteinase-3 (MMP-3) and glutaminyl cyclase (QC) implicated in its formation—in
AD and in the transgenic Tg2576 AD mouse model. In the human brain, pGlu79-aSyn was detected
in cortical pyramidal neurons, with more distinct labeling in AD compared to control brain tissue.
Using immunohistochemical double and triple labelings and confocal laser scanning microscopy, we
demonstrate an association of pGlu79-aSyn, MMP-3 and QC with β-amyloid plaques. In addition,
pGlu79-aSyn and QC were present in amyloid plaque-associated reactive astrocytes that were also
immunoreactive for the chaperone heat shock protein 27 (HSP27). Our data are consistent for the
transgenic mouse model and the human clinical condition. We conclude that pGlu79-aSyn can
be generated extracellularly or within reactive astrocytes, accumulates in proximity to β-amyloid
plaques and induces an astrocytic protein unfolding mechanism involving HSP27.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:87883 |
| Date | 03 November 2023 |
| Creators | Bluhm, Alexandra, Schrempel, Sarah, Schilling, Stephan, von Hörsten, Stephan, Schulze, Anja, Roßner, Steffen, Hartlage-Rübsamen, Maike |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1006 |
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