Blood-brain barrier dysfunction in Alzheimer’s Disease (AD)
The blood-brain barrier (BBB) is formed by a continuous layer of cerebral endothelial cells held together by tight junction proteins (TJP), which restrict the movement of molecules. BBB dysfunction is an early biomarker of cognitive impairment, occurring during the early clinical stages of AD . Loss of TJP expression and breakdown of the BBB is associated with the accumulation of serum proteins normally excluded from the CNS, which may stimulate a neuroinflammatory response and further contribute to disease pathogenesis .
ApoE-ε4 induced BBB dysfunction
Possession of one or two ApoE-ε4 alleles is a major risk factor for developing AD, and leads to accelerated breakdown of the BBB . Magnetic resonance imaging studies have shown that individuals with at least one ε4 allele display more BBB dysfunction in the hippocampus and temporal cortex than those without an ε4 allele . Furthermore, dysfunction of the BBB is detected in cognitively normal individuals who possess an ε4 allele, and more severe in those with cognitive impairment , however the mechanism(s) underlying this dysfunction is currently unknown.
miRNAs impact BBB integrity
microRNAs (miRNAs) are small, non-coding RNAs which target molecules in a sequence-specific manner to modulate messenger RNA (mRNA) expression. miRNAs are linked to pathologically relevant mechanisms, including BBB dysfunction . We have previously characterised the detailed neuropathology of an ageing cohort and demonstrated BBB dysfunction in the normal ageing process , and assessed age-associated changes in the transcriptomic and miR profile of the neurovascular unit, identifying biologically relevant age-associated RNA changes which impact BBB function and modulate the neuroinflammatory response . Similar detailed studies in AD are required, as the modulation of miRNA expression represents a potential therapeutic strategy for restoring BBB integrity in AD.
We hypothesise that ApoE-ε4 induced miRNA/mRNA network changes impact BBB integrity and contribute to cognitive decline in AD. The proposed study aims to identify the potential mechanism(s) underlying ApoE-ε4 associated vascular pathology in AD. Specifically, this study aims to
- Histologically assess BBB dysfunction in control and AD cases, both with and without ApoE-ε4
- Characterise ApoE-ε4 associated miRNA and mRNA changes in the BBB using RNAseq
- Interrogate the bioinformatic datasets to identify biologically relevant miRNA and mRNA candidates, and validate the findings both at the protein level (by immunohistochemistry) and RNA (by digital PCR)
This study will provide a greater understanding of the ApoE-ε4 induced mRNA/miRNA network changes that occur and may help to develop novel therapies to restore BBB integrity in AD.