Open Collections

Mechanism underlying dysregulated cerebral vessel growth in Alzheimer’s disease

University of British Columbia

Alzheimer’s disease (AD), a neurodegenerative disorder of the elderly, causes loss of memory leading to dementia. The exact cause of this disease is still unknown, and the mechanism of pathogenesis highly debated. Amyloid beta (Aβ) peptide is central to the disease along with the cerebrovascular dysfunction and impaired cerebral blood flow (CBF). A strong link exitsts between brain vascular dysfunction and AD. This link was established due to evidence of reduced blood-brain barrier (BBB) integrity preceding various AD neuropathologies. Furthermore, BBB dysfunction could influence CBF, which in turn influences blood vessel growth. Current dogma holds that BBB leakiness is likely due to vascular deterioration. Inflammatory changes in the AD brain lead to up-regulation of mediators like, VEGF and Tie-2, that initiate angiogenesis. Studies indicate pathological angiogenesis and BBB disruption occur as a compensatory response to impaired CBF. Aβ-induced neuroinflammatory responses promote the generation of reactive oxygen species and further endothelial damage. Aβ is shown to be a modulator of blood vessel density and vascular remodeling via angiogenic mechanisms. Studies on the cerebrovascular integrity in AD model mice showed a significant increase in the incidence of disrupted tight junctions which is directly linked to an increase in microvascular density. This strongly supports amyloidgenesis-triggered angiogenesis as the basis of BBB disruption. This thesis aims in attempting to curb vascular damage seen in the brains of AD mice and improve cognition by treating them with anti-angiogenic drugs providing scope for these to modulate cerebral angiogenesis to ameliorate Aβ load, reduce vasculature damage and reverting cognitive decline. This may facilitate new preventive and therapeutic interventions for not only AD but also related vascular diseases such as small vessel disease. As a part of the study, a mechanism for vascular dysfunction in AD is proposed as follows: Aβ triggers dysregulated blood vessel growth via Angiopoietin-2 mediated activation of the Tie-2 receptor of the angiogenesis pathway. Also demonstrated in this thesis is that AD pathology can be established by a bone marrow transplant from an AD mouse model into an APP knockout mouse suggesting the role of soluble Aβ in AD pathogenesis.

Text

2020-05-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/70005

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/