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  Glial and vascular contributions to neurodegenerative diseases
  double immunofluorescence and proximity ligation assays.
Results: For the first time, we observed that treatment with PA8 improves memory functions of 5XFAD mice. Mechanistically, we found that PA8 significantly reduces AβO-PrP interaction and its downstream signaling such as activated Fyn kinase, reactive gliosis (astrocytes and microglia) and its associated neurodegeneration in the cortical and hippocampus regions of brain tissue of 5XFAD mice.
Discussion: Our results indicate that treatment with PA8 targeting the AβO-PrP-Fyn axis and reduces activated gliosis mediated neurodegeneration and subsequently improves memory function in 5XFAD transgenic mouse model. This study proves that PA8 is valuable tool to be explored as a treatment for AD. PA8 is stable, specific and non- toxic therapeutic with advantage of low-cost, high-yield production compared to other protein-based therapeutics such as monoclonal antibodies.
Conclusion: In vitro and in vivo results demonstrate that PA8 might be valuable as emerging/promising and novel therapeutic to treat AD.
on global cognitive functioning (β±SE=1.31±0.61,P=0.032), executive functioning (β±SE=0.24±0.12, P=0.045), and attention and speed (β±SE=0.26±0.13,P=0.049). Levels of all other biomarkers did not associate with cognitive performance.
Conclusion: We observed highly variable levels of blood-based biomarkers in centenarians. Apart from the Aβ42/40 ratio, other plasma biomarkers did not correlate with cognitive performance. This suggests that plasma concentrations of pTau-181, NfL and GFAP are less fit biomarkers to measure changes in cognitive performance in the oldest old.
Background: Women run two-to-three-fold higher risk of developing Alzheimer’s disease (AD) than men, which cannot simply be attributed to their greater longevity [1]. Importantly, the female sex hormone estrogen is well established to exert neuroprotective properties [2], and this protection is lost at menopause [3]. Although, perimenopausal estrogen supplementation may serve as a good strategy to prevent neurodegeneration, its effects have been unclear. Increasing evidence put forward the estrogen receptor-β (ERβ) as an important protective player in AD pathology [4] and loss of ERβ results in progressive neural cell body degeneration [5]. However, the exact mechanism remains poorly understood. Since neuroinflammation and microglial activation is a hallmark of AD, we sought to investigate the effect of estrogen signaling and ERβ in microglial function.
Materials and Methods: Primary microglia from WT and ERβ-Knock- Out mice were isolated and examined for their activation and cytokine profile, and compared with microglial activation in the APPNL-G-F Knock-In AD mouse model treated with or without an ERβ-selective ligand (LY500307).
Results: Our findings suggest that loss of ERβ results in an increased neuroinflammatory profile, associated with altered migration and phagocytosis, indicating a more activated phenotype possibly in a sex- specific manner. LY500307 treatment led to less amyloid plaques and better memory performance in both male and female APP-KI mice, which could be ascribed to altered APP-processing. Additionally, cortical gene expression analysis demonstrated that proinflammatory markers are differently regulated upon ovariectomy and ERβ-stimulation. Discussion and Conclusions: Although, we are at an early stage in understanding the estrogenic impact on microglia, our study demonstrates that ERβ has a modulatory role on microglial function and offers neuroprotection in the APP-KI mice. Thus, ERβ may be a potential modulator of neuroinflammation in AD. Such knowledge can pave the way in designing novel personalized and sex-specific therapeutic interventions, targeting ERβ, to combat AD.
Levels of AD associated plasma biomarkers increase with age which may obscure an association with cognitive performance in the oldest old
Linda Lorenz1,2,3, Meng Zhang1,4, Niccolo Tesi1,4, Sven Van der Lee1,2,3, Marc Hulsman1,2,4, Mariam Gouda5, Sietske Sikkes1,6,7, Charlotte Teunissen5, Henne Holstege1,2,3,4
1Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands, Amsterdam,
The Netherlands, 2Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands, Amsterdam, The Netherlands, 3Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands, Amsterdam, The Netherlands, 4Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands, Delft, The Netherlands, 5Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands, Amsterdam, The Netherlands, 6Department of Epidemiology & Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands, Amsterdam, The Netherlands, 7Faculty of Behavioural and Movement Sciences, Clinical Developmental Psychology and Clinical Neuropsychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands, Amsterdam, The Netherlands
 Background: Changes in blood-based biomarker levels of amyloid-β40, amyloid-β42, pTau-181, neurofilament light and glial fibrillary acidic protein in old-aged individuals can associate with poorer cognitive performance. However, levels of plasma biomarkers increase with age in cognitively healthy individuals. Here we investigate whether, with increasing age over 100 years, the association between levels of plasma biomarkers and cognitive performance remains.
Methods: We included 202 cognitively healthy centenarians from the Dutch 100-plus Study and 317 children or siblings from centenarians, and their partners. Cognitive functioning was evaluated in centenarians using a comprehensive neuropsychological assessment, while the other participants were presumed cognitively healthy. Plasma was collected at time of neuropsychological assessment and was measured on the Simoa platform. All plasma levels were divided into tertiles. Associations between plasma biomarkers and cognitive functioning were evaluated using multiple regression analyses per tertile, using tertile 1 as a reference while adjusting for age, sex and education.
Results: We observed an age-related increase (Aβ40, Aβ42, pTau-181, NfL and GFAP) or decrease (Aβ42/40 ratio). Between individuals, levels of plasma biomarkers varied greatly. However, plasma biomarker concentrations intercorrelated between individuals: Aβ40 (r=0.71, range 46.53-287.54 pg/mL), Aβ42 (r=0.56, range 1.38-17.67 pg/mL), Aβ42/40 ratio (r=-0.42, range 0.001-0.100 pg/mL), pTau181 (r=0.63, range 0.54-12.75 pg/mL), NfL (r=0.59, range 4.51-378.65 pg/mL) and GFAP (r=0.66, range 24.39-1085.09 pg/mL). Only lower ratios of plasma Aβ42/40 were weakly associated with worse cognitive performance
Although all Alzheimer’s disease (AD) patients have plaques, not all plaques are the same. We recently described the coarse-grained plaque
Estrogen receptor beta modulates microglia activation in Alzheimer’s disease pathology Aphrodite Demetriou1, Mukesh Varshney1, Ivan Nalvarte1 1Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
The coarse-grained plaque is an aberrant Aβ plaque associated with astrogliosis and pTau burden in APOE4 Alzheimer’s disease
Baayla D.C. Boon1, Naomi Kouri1, Sydney A. Labuzan1, Jessica F. Tranovich1, Isabelle Frankenhauser2, Christian Lachner1, Nilüfer Ertekin-Taner1, Ranjan Duara2,
Neill R Graff-Radford1, Dennis W Dickson1, Melissa Murray1
1Mayo Clinic, Jacksonville, USA, 2Parcelsus Medical University, Austria, 3Mount Sinai Medical Center, Miami, USA
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