Alzheimer’s Amyloid β Peptide Induces Angiogenesis in an Alzheimer’s Disease Model Mouse through Placental Growth Factor and Angiopoietin 2 Expressions

Abstract

Increased angiogenesis, especially the pathological type, has been documented in Alzheimer’s disease (AD) brains, and it is considered to be activated due to a vascular dysfunction-mediated hypoxic condition. To understand the role of the amyloid β (Aβ) peptide in angiogenesis, we analyzed its effects on the brains of young APP transgenic AD model mice. Immunostaining results revealed that Aβ was mainly localized intracellularly, with very few immunopositive vessels, and there was no extracellular deposition at this age. Solanum tuberosum lectin staining demonstrated that compared to their wild-type littermates, the vessel number was only increased in the cortex of J20 mice. CD105 staining also showed an increased number of new vessels in the cortex, some of which were partially positive for collagen4. Real-time PCR results demonstrated that placental growth factor (PlGF) and angiopoietin 2 (AngII) mRNA were increased in both the cortex and hippocampus of J20 mice compared to their wild-type littermates. However, vascular endothelial growth factor (VEGF) mRNA did not change. Immunofluorescence staining confirmed the increased expression of PlGF and AngII in the cortex of the J20 mice. Neuronal cells were positive for PlGF and AngII. Treatment of a neural stem cell line (NMW7) with synthetic Aβ1–42 directly increased the expression of PlGF and AngII, at mRNA levels, and AngII at protein levels. Thus, these pilot data indicate that pathological angiogenesis exists in AD brains due to the direct effects of early Aβ accumulation, suggesting that the Aβ peptide regulates angiogenesis through PlGF and AngII expression.

Elevated CSF angiopoietin-2 correlates with blood-brain barrier leakiness and markers of neuronal injury in early Alzheimer’s disease.

“…ANGPT2 level was reported to be elevated in microvessels enriched from post-mortem AD brain tissue compared to healthy age-matched controls (16). ANGPT2 expression was elevated in young 2-month-old APP over-expressing J20 mice at an age when markers of pathological angiogenesis and increased vessel density were also observed suggesting that ANGP2 contributes to vascular instability in early AD (20). Our ndings are in keeping with other evidence that damage to the cerebral vasculature occurs early in the development of AD.…”

“…CSF α-synuclein was also found to be raised in early AD and to be related to cognitive decline (29). ANGPT2 was recently shown to be elevated in cortical neurones in young 2-month old J20 mice with evidence of pathological angiogenesis and was induced in response to Aβ peptides in neural stem cells suggesting that Aβ-induced ANGPT2 expression within neurons contributes to vascular instability in early AD (20). Together, these data highlight the linkage between neuroin ammation, cerebral vascular injury, and neurodegeneration in AD.…”

“…In the rodent model, recombinant ANGPT2 triggered pericyte loss and vascular instability (15). ANGPT2 expression was elevated in microvessel-enriched preparations of brain tissue in AD (16), in which pericyte loss and BBB leakiness have been reported at an early disease stage (17)(18)(19) and was elevated concurrently with markers of angiogenesis in the cortex of young (2 month) J20 APP over-expressing mice (20).…”

The Role of the Vascular System in Degenerative Diseases: Mechanisms and Implications

“…The vascular system plays a crucial role in multiple physiological processes throughout the body [4]. Dysfunctional vascular mechanisms often contribute to the initiation and exacerbation of diseases [5][6][7], highlighting the intricate relationship between vascular health and overall well-being. Disturbances in the vascular system can manifest as diseases of specific systems, such as the nervous system or kidney system [5][6][7].…”

“…Dysfunctional vascular mechanisms often contribute to the initiation and exacerbation of diseases [5][6][7], highlighting the intricate relationship between vascular health and overall well-being. Disturbances in the vascular system can manifest as diseases of specific systems, such as the nervous system or kidney system [5][6][7]. Conversely, conditions of a specific system can reciprocally affect the vascular system [8,9].…”