L-type calcium channel blockers and substance P induce angiogenesis of cortical vessels associated with beta-amyloid plaques in an Alzheimer mouse model

Abstract

It is well established that L-type calcium channels (LTCCs) are expressed in astroglia. However, their functional role is still speculative, especially under pathologic conditions. We recently showed that the α1 subunit-like immunoreactivity of the CaV1.2 channel is strongly expressed in reactive astrocytes around beta-amyloid plaques in 11-month-old Alzheimer transgenic (tg) mice with the amyloid precursor protein London and Swedish mutations. The aim of the present study was to examine the cellular expression of all LTCC subunits around beta-amyloid plaques by in situ hybridization using 35S-labeled oligonucleotides. Our data show that messenger RNAs (mRNAs) of the LTCC CaV1.2 α1 subunit as well as all auxiliary β and α2δ subunits, except α2δ-4, were expressed in the hippocampus of age-matched wild-type mice. It was unexpected to see, that cells directly located in the plaque core in the cortex expressed mRNAs for CaV1.2 α1, β2, β4, and α2δ-1, whereas no expression was detected in the halo. Furthermore, cells in the plaque core also expressed preprotachykinin-A mRNA, the precursor for substance P. By means of confocal microscopy, we demonstrated that collagen-IV-stained brain vessels in the cortex were associated with the plaque core and were immunoreactive for substance P. In cortical organotypic brain slices of adult Alzheimer mice, we could demonstrate that LTCC blockers increased angiogenesis, which was further potentiated by substance P. In conclusion, our data show that brain vessels associated with beta-amyloid plaques express substance P and an LTCC and may play a role in angiogenesis.

Amyloid β‐induced astrogliosis is mediated by β1‐integrin via NADPH oxidase 2 in Alzheimer's disease

“…The primary goal of the current study was to unmask the molecular players that contribute to the dysregulation of astrocyte physiology during AD progression. It is well known in these cells that Aβ promotes calcium imbalance by mechanisms that involve endoplasmic reticulum activation and stress (Alberdi et al ., ), regulation of L‐type calcium channel expression (Daschil et al ., ), and calcium‐sensing receptor activation (Chiarini et al ., ). In addition to these activities, the glial cellular stress generated via NOX enzyme activities may contribute to leading glia‐mediated neurotoxicity in AD (Angelova & Abramov, ).…”

Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling

“…This study took advantage of the OBSC system to explore mechanisms of pathological angiogenesis that are difficult to study in vivo. OBSCs are a potent, underused tool for exploring vascular phenotypes 23,36,37 with few prior studies seeking to explore this in combination with AD models 32,38 . Interestingly, the increased sprouting angiogenesis we observed in TgCRND8 OBSCs is more pronounced than we find in vivo at a similar age.…”

Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signaling

“…OBSCs represent a potent tool for exploring vascular phenotypes in a system that retains native cell populations and cytoarchitecture, Until now, whilst the OBSC model has been well established for studying angiogenic processes, (33), (34), (20), there were few studies seeking to explore this in combination with AD models. Slices from adult APP_SweDI mice have been found to express L-type calcium channels and substance P around amyloid plaques, pointing to altered angiogenesis at this key pathological site (35). Another study demonstrated that platelets from an AD mouse model damage healthy cortical vessels and induced Aβ accumulation when infused into wildtype OBSC vessels (28).…”