Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

Abstract

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.

Vascular Endothelial Cells: Heterogeneity and Targeting Approaches

“…"AAV-BR1", another AAV capsid mutant isolated from our AAV2 library which displays the peptide "NRGTEWD", mediates homing to ECs of the central nervous system (brain, spinal cord and retina) [194]. AAV-BR1 has been applied in various studies to assess the role of brain or retina ECs in different physiological and pathophysiological settings [336][337][338][339][340][341][342][343] and it has successfully been used in mouse models to treat the neurological impairments of incontinentia pigmenti [194,195] and Sandhoff disease [196]. In our view, the above-mentioned examples demonstrate huge experimental and therapeutic potential of AAV display peptide libraries and phage display libraries alike and both techniques will likely yield targeting peptides for additional EC subpopulations in the future.…”

Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer’s disease pathology and in human post-mortem brain samples

“…This change may be attributed to the genotype rather than the cellular state, as all microglia (both typical and dark) observed in the APP-PS1 mice interacted signi cantly less with the vasculature compared to C57BL/6J typical microglia, regardless of their distance to Aß plaques and dystrophic neurites (NDM 3.571 ± 3.571% vs CTM 33.33 ± 9.245%, p = 0.0038; NTM 3.704 ± 3.704% vs CTM 33.33 ± 9.245%, p = 0.0045; FTM 6.897 ± 4.789% vs CTM 33.33 ± 9.245%, p = 0.0133) (Figure 3 G). This drastic difference in dark microglial vascular interactions observed in the aged APP-PS1 mice compared to the controls could be associated with a previously observed reduced volume of cerebral vasculature near Aß plaques, a phenomenon suggested to be caused by nonproductive angiogenesis resulting in vascular scars near Aß plaques (103).…”

Associations of plasma angiostatin and amyloid-β and tau levels in Alzheimer’s disease

“…The relationship between blood angiostatin levels and AD is controversial. In addition, a previous study found that Aβ could promote extensive neoangiogenesis leading to increased hypervascularization [ 24 ], while the cerebral microvasculature was shown to be reduced around Aβ plaques [ 25 ]. Hence, the role of Aβ in angiogenesis and how angiogenesis may contribute to the pathogenesis of AD remain unclear.…”