Immune-mediated platelet depletion augments Alzheimer’s disease neuropathological hallmarks in APP-PS1 mice

Abstract

In Alzheimer's disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. Here, we depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaqueassociated neuritic dystrophy and gliosis. In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In plateletdepleted females, plaque-associated Iba1+ microglia had lower amounts of fibrillar amyloid beta cargo and GFAP+ astrocytic processes showed a higher overlap with thioflavin S+ amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, our data suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated.

Circulating Platelets Modulate Oligodendrocyte Progenitor Cell Differentiation During Remyelination

“…To investigate whether circulating platelets modulate OPC function in vivo , we used a platelet depletion model (Figure 2A). LPC-induced focal demyelinating lesions were performed in WT mice followed by the administration of anti-CD42b at 3 dpl and every second day to prevent further platelet recruitment (Morodomi et al ., 2020; de Sousa et al ., 2023). We first confirmed that this depletion strategy leads to decreased numbers of recruited platelets, with no accumulation in the lesion (p-value < 0.05) (Figure 2B).…”

The adhesion GPCR ADGRV1 controls glutamate homeostasis in hippocampal astrocytes supporting neuron development: first insights into to pathophysiology ofADGRV1-associated epilepsy

“…In the brain, ADGRV1 is strongly expressed in neurons, but highest in astrocytes (McMillan and White, 2010) Here, we observed that deficiency of ADGRV1 leads to decreased abundance and altered morphology of astrocytes in the CA1 region of the hippocampus, most likely due to an imbalanced glutamate homeostasis. Corresponding changes in astrocyte morphology and number have been observed in diseases in which astrocytes are known to be involved in the pathogenesis such as acute brain trauma and chronic neuropathies, e.g ., Alzheimer’s disease, but also in the development of epilepsy (Wu et al, 2021; Hayashi et al, 2022; de Sousa et al, 2023). The increase in branching or convex hull area of astrocytes is thought to be a consequence of the reduced number of cells in the diseased brain due to their exploratory attempts to contact the remaining neurons.…”

Correlation analysis of peripheral platelet markers and disease phenotypes in Alzheimer's disease

“…However, other studies have indicated that short‐term platelet depletion may promote amyloid plaque growth, increase the risk of neuroinflammatory dystrophy, affect microglial phagocytosis, and alter astrocyte morphology in the hippocampus of female APP‐PS1 mice. 13 , 14 The precise relationship between platelet count and the underlying molecular mechanisms regulating amyloid plaque deposition remains elusive and needs to be further investigated in future experiments.…”