Biology subjects

Donner, L.

Publications and source records attributed to Donner, L..

4 recordsLinked to original sources

bioRxiv2025

Elevated IL-1 beta plasma levels, altered platelet activation and cardiac remodeling lead to moderately decreased LV function in Alzheimer transgenic mice after myocardial ischemia and reperfusion

IntroductionNeurodegeneration and dementia are key factors in Alzheimers disease (AD). The deposition of amyloid-{beta} into senile plaques in the brain parenchyma and in cerebral vessels known as cerebral amyloid angiopathy (CAA) are the main clinical parameters of AD. Acute myocardial infarction (AMI) and AD share a comparable pathophysiology. In detail, AMI survivors have a higher risk of vascular dementia and AD patients with AMI face a poor prognosis with a high rate of major adverse cardiovascular events. High blood levels of amyloid-{beta}40 are identified in patients with high risk for cardiovascular death. However, the underlying mechanisms and the consequences of AMI in AD patients are unclear to date. MethodsAD transgenic APP23 mice were analysed in an experimental AMI using the closed-chest model. ResultsAPP23 mice displayed significantly decreased left ventricular function as detected by FS/MPI (fractional shortening/myocardial performance index) after 24 h and 3 weeks after ligation of the LAD compared to WT controls. No differences have been observed in infarct and scar size. However, the analysis of cardiac remodeling after 3 weeks showed an altered composition of the collagen tissue of the scar with elevated tight but reduced fine collagen in APP23 mice. Altered scar formation was accompanied by elevated degranulation of platelets following activation of the collagen receptor GPVI. ConclusionThe here presented results suggest that AD patients are at higher risk for cardiac damage after AMI that might increase the risk for cardiovascular death. This implies the need of a personalized therapy of AMI in AD patients.

neuroscience↗

bioRxiv2025

Platelets from early-stage Alzheimer patients show enhanced amyloid binding, an elevated open canalicular system and sex-specific differences in their activation profile

IntroductionAlzheimers disease (AD) is associated with neurodegeneration and dementia. The clinical parameters include the deposition of amyloid-{beta} into senile plaques in the brain parenchyma and in cerebral vessels known as cerebral amyloid angiopathy (CAA). Currently, {beta}-amyloid-antibodies are emerging as possible therapy for AD. Several biomarkers, such as {beta}-Amyloid and tau-protein have gained significant value for diagnosing early AD. However, these biomarkers require cerebrospinal fluid. Blood tests for screening of AD are urgently needed. MethodsPatients diagnosed with early AD were analyzed for extracellular amyloid-{beta} binding to platelets, platelet morphology and platelet activation and compared to age-matched controls. ResultsBeside unaltered platelet number and size, we detected increased binding of amyloid-{beta} to activated platelets isolated from AD patients. Electron microscopy revealed an altered platelet morphology in AD patients including the number of dense granules and the area of the open canalicular system (OCS) as compared to controls. While only minor differences in platelet activation were detected between patients and controls, a significant reduction of integrin IIb{beta}3 (fibrinogen receptor) activation was evident in platelets from female compared to male AD patients as determined by flow cytometry. ConclusionThe here presented results emphasize the importance to increase our understanding how platelets contribute to AD pathology in patients in a sex-specific manner. Furthermore, platelet parameters might serve as an ideal biomarker for a first prognosis of AD because platelets can be easily accessed by blood samples. These parameters might include a sex-specific platelet activation profile, the capability to bind A{beta} to the platelet surface and the dimension of the OCS by electron microscopy.

neuroscience↗

bioRxiv2025

Long-term antiplatelet therapy protects against cerebral but not parenchymal amyloid plaque formation and neurodegeneration in transgenic mice of Alzheimers disease

IntroductionCerebral amyloid angiopathy (CAA) is characterized by the aggregation of amyloid-{beta} peptides in cerebral blood vessels, leading to a loss of vascular integrity and contributing to the progression of Alzheimers disease (AD). In our previous study, we showed that short-term treatment with the antiplatelet drug clopidogrel, a P2Y12 inhibitor that irreversibly blocks ADP signaling, reduced the incidence of CAA in the APP23 mouse model of Alzheimers disease providing strong evidence for platelets to contribute to AD pathology. The objective of the present study was to ascertain whether long-term treatment with clopidogrel and the earlier initiation of treatment prior to the formation of A{beta} deposits prevents pathological changes associated with Alzheimers disease. MethodsAPP23 mice were treated with clopidogrel for 15 month and analyzed for AD pathology. ResultsWe detected increased permeability of the blood brain barrier in different brains regions of APP23 mice. Moreover, platelets migrated into the brain parenchyma and accumulated around amyloid plaques in the brain of APP23 mice. Although we detected platelets in close proximity to microglia and neurons in the cortex and hippocampus of APP23 mice, we did not observe any differences in neurodegeneration or gliosis in Clopidogrel treated APP23 mice. Furthermore, pathological analysis showed a significant reduction in CAA and in soluble A{beta}42 levels in the brain of Clopidogrel versus placebo treated APP23 mice but no differences in plaque load in the brain parenchyma. ConclusionThus, antiplatelet therapy may alleviate amyloid pathology in cerebral vessels leading to improved blood perfusion in AD patients.

pathology↗

bioRxiv2023

Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer's Disease Mouse Models

The development of novel drugs for Alzheimers disease has proven difficult, with a high failure rate in clinical trials. Typically, transgenic mice displaying amyloid-{beta} peptide brain pathology are used to develop therapeutic options and to test their efficacy in preclinical studies. However, the properties of A{beta} in such mice have not been systematically compared to A{beta} from the patient brains. Here, we determined the structures of nine ex vivo A{beta} fibrils from six different mouse models by cryo-EM. We found novel A{beta} fibril structures in the APP/PS1, ARTE10, and tg-SwDI models, whereas the human familial type II fibril fold was found in the ARTE10, tg-APPSwe, and APP23 models. The tg-APPArcSwe mice showed an A{beta} fibril whose structure resembles the human sporadic type I fibril. These structural elucidations are key to the selection of adequate mouse models for the development of novel plaque-targeting therapeutics and PET imaging tracers. One Sentence SummaryCryo-EM structures of A{beta} fibrils extracted from brains of mouse models used for Alzheimers disease preclinical research are presented.

neuroscience↗