Alzheimer's disease copathology in dementia with Lewy bodies is associated with astroglial α-synucleinopathy

Geut, H.; van den Berg, E.; Boon, B. D.; Hoozemans, J. J.; Tunold, J.-A.; Pihlstrom, L.; Jonkman, L. E.; Rozemuller, A. J.; Lemstra, E. A.; van de Berg, W. D. J.

doi:10.1101/2024.01.02.573857

bioRxiv · 10.1101/2024.01.02.573857

Alzheimer's disease copathology in dementia with Lewy bodies is associated with astroglial α-synucleinopathy

Geut, H.·van den Berg, E.·Boon, B. D.·Hoozemans, J. J.·Tunold, J.-A.·Pihlstrom, L.·Jonkman, L. E.·Rozemuller, A. J.·Lemstra, E. A.·van de Berg, W. D. J.

View original source ↗Export metadata ↓

Abstract

BackgroundIn dementia with Lewy bodies (DLB), co-existence of Alzheimers disease (AD) pathology, i.e. amyloid-{beta} plaques and tau tangles, has been associated with a more rapid disease progression. In post-mortem DLB brains, we examined the association between AD copathology and regional load and morphology of -synuclein pathology. Also, we compared regional load and morphology of AD copathology in DLB to pathology in AD. MethodsWe included 50 autopsy-confirmed DLB donors with a clinical DLB phenotype, categorized as having no/low levels of AD copathology (pure DLB, n = 15), or intermediate/high levels of AD copathology (mixed DLB+AD, n = 35), and autopsy-confirmed pure AD donors (n = 14) without - synuclein pathology. We used percentage area of immunopositivity for quantitative assessment of pathology load, and visual scores for semi-quantitative assessment of different morphologies of - synuclein, amyloid-{beta} and phosphorylated tau (p-tau) pathology in fifteen neocortical, limbic and brainstem regions. ResultsMixed DLB+AD compared to pure DLB showed a shorter disease duration (6 {+/-} 3 versus 8 {+/-} 3 years, p = 0.021) and higher frequency of APOE-{varepsilon}4 alleles. A-synuclein load was higher in neocortical regions (temporal, parietal and occipital), but not in brainstem and limbic regions, which was based upon an increase of Lewy bodies, -synuclein-positive astrocytes and -synuclein-positive plaques in these regions. A-synuclein load was most strongly correlated to amyloid-{beta} and p-tau load in temporal (r = 0.38 and r = 0.50 respectively) and occipital regions (r = 0.43 and r = 0.42 respectively). Compared to pure AD, mixed DLB+AD showed a lower amyloid-{beta} load in temporal cortex, CA3 and CA4 region, and lower p-tau loads in frontal and parietal cortex, based both upon presence of fewer neuritic plaques as well as neurofibrillary tangles. ConclusionsIn DLB brains, AD copathology was associated with more neocortical -synuclein pathology, consisting not only of Lewy bodies and plaques, but also of astroglial -synuclein. AD pathology in DLB cases is less than in AD cases, reflecting less advanced pathological stages. Astroglial -synuclein and its relation with AD copathology in DLB should be further studied, as this may play a role in accelerating clinical decline.

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Geut, H., van den Berg, E., Boon, B. D., Hoozemans, J. J., Tunold, J.-A., Pihlstrom, L., Jonkman, L. E., Rozemuller, A. J., Lemstra, E. A., van de Berg, W. D. J.. 2024-01-02. Alzheimer's disease copathology in dementia with Lewy bodies is associated with astroglial α-synucleinopathy. https://doi.org/10.1101/2024.01.02.573857

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Autophagic flux is increased in peripheral blood mononuclear cells in atherosclerotic vascular disease and associates inversely with adverse cardiovascular events

Background: Autophagy is a homeostatic pathway supporting stress adaptation and is dysregulated in atherosclerosis. Its potential as a biomarker or therapeutic target in atherosclerotic vascular disease (ASVD) remains incompletely defined. We measured autophagic flux in peripheral blood mononuclear cells (PBMCs) from patients with peripheral arterial disease (PAD) or carotid stenosis (CS), compared with healthy controls, and explored clinical outcome associations. Methods: Ninety-four patients with PAD or CS and 19 healthy controls were studied. Autophagic flux was quantified from fresh blood using a validated ex vivo chloroquine inhibition ELISA measuring LC3BII accumulation. Major adverse cardiovascular events (MACE) and major adverse limb events (MALE) were ascertained over a median follow up of 828 days. Results: The ASVD cohort comprised claudication (n = 16), chronic limb threatening ischemia (CLTI; n = 49), and CS (n = 29). Autophagic flux was higher in ASVD than controls (mean 281.4 vs. 182.3 ng LC3BII/mg protein/h; p < 0.0001) and remained independently associated after multivariable adjustment. Within CLTI, concurrent infection was associated with lower flux (p = 0.001), approaching control levels (p = 0.327). In CLTI, higher flux quartiles were associated with lower MACE risk, most strongly for quartile 3 (hazard ratio 0.07 vs. quartile 1, 95% CI 0.01 to 0.50; p = 0.009). Conclusion: Autophagic flux is elevated in PBMCs from ASVD patients, independent of age and sex. Attenuated flux in CLTI with concurrent infection may indicate autophagic exhaustion in advanced disease. The association between higher flux and lower MACE in CLTI suggests prognostic utility, warranting evaluation in larger prospective studies.

pathology↗

bioRxiv2026

Quantitative Model of the Ocular Immune Response during Seasonal Allergic Conjunctivitis

Allergic conjunctivitis is an inflammation of the conjunctiva caused by allergen; it is common disorder affecting up to 40% of the population. In this work, we study seasonal allergic conjunctivitis (SAC), also called "hay fever eyes", which is caused by exposure to airborne pollens. We develop a mathematical model quantifying the ocular immune system response to the allergens. First, we present a simplified qualitative description of the immunopathogenesis of SAC. Then, we express each chosen immunopathological mechanism mathematically to construct a system of thirty-one ordinary differential equations. We compare summary statistics of the predicted observable immune signals to experimental measurements and find our model captures key qualitative features of SAC progression. We then compare our predicted time series of histamine concentration to symptom scores and find a strong correlation suggesting the model predicts relevant clinically trends. Next, we calibrate the model through multi-step process. We find the most influential parameters are the production and depletion rates of IL-4, and the production rates of IL-5 and IL-8. These cytokines are targeted in treatments for asthma, atopic dermatitis, and severe eosinophilic associated disorder and suggest potential therapeutic targets for SAC. Our calibrated model mimics most of the summary statistics of the experimentally observable immune signals with discrepancies for IL-5 and IL-13 indicating that additional immunopathological mechanisms could be important.

pathology↗

bioRxiv2026

Dysregulated Platelet GPIb alpha - VWF Signalling in Abdominal Aortic Aneurysm formation and Progression

Background: Platelets are critical drivers of thrombo-inflammatory responses in different cardiovascular diseases. Abdominal aortic aneurysm (AAA) is a progressive, life-threatening vascular disorder mainly characterised by chronic inflammation, extracellular matrix degradation, and the formation of a platelet-rich intraluminal thrombus (ILT). Experimental and clinical evidence identified platelets as main players in AAA pathology as evidenced by elevated platelet activation and procoagulant activity that critically contribute to AAA progression. Methods: The present study investigated the contribution of glycoprotein (GP)Ib alpha, the von Willebrand factor (VWF)-binding subunit of the platelet GPIb-IX-V complex, to AAA initiation and progression in experimental AAA using the ePPE mouse model and in patients. Results: Genetic ablation of platelet GPIb alpha significantly attenuated early aneurysm expansion in experimental AAA, indicating a critical role for GPIb alpha during the initial stages of aneurysm development. This initial effect was compensated at later time points showing no differences in aneurysm progression between groups. Notably, genetic deletion of GPIb alpha induced a constitutively hyperactive platelet phenotype already in naive mice that was further amplified during experimental AAA. This elevated platelet hyperactivity was mainly due to increased GPVI activation of platelets 28 days post-surgery. To assess the clinical relevance, spatial profiles of human ILT specimens from patients with AAA were analysed. In the ILT, we detected a highly compartmentalised distribution of GPIb alpha and VWF with pronounced enrichment within the luminal layer. In parallel, circulating VWF activity as well as platelet surface expression of GPIb alpha were significantly increased in patients with AAA. Conclusion: Collectively, these findings identify a dysregulated GPIb alpha-VWF axis in human AAA pathology, mainly characterised by enhanced platelet GPIb alpha surface expression and increased activity of circulating VWF.

pathology↗