Research

STRATEGIES FOR IMPROVING IPAD

Agents that improve contractility of vascular smooth muscle cells

Phosphodiesterase III is the major cAMP-hydrolyzing PDE uniquely expressed in vascular smooth muscle cells; PDE IIIA isoforms are also involved in cardiovascular function by regulating vascular smooth muscle growth and phenotypic changes. Cilostazol is a selective inhibitor of PDE III that increases cAMP in vascular cells and has multiple effects on the vasculature such as vasodilatation, anti-oxidation, anti-inflammation, regulation of smooth muscle cells, increase in cerebral haemodynamics and arterial elasticity with maintenance of microvascular integrity, as reviewed in (19). Cognition is significantly improved in experimental models and in humans receiving Cilostazol (20)(21)(22)(23). Administration of Cilostazol significantly improves IPAD and the brains of mice treated with Cilostazol show effects upon extracellular matrix, with upregulation of the anti-fibrillogenic glycoproteins (24)(25).

 

Using chaperones for efficient transport along the IPAD pathways

Clusterin (Apolipoprotein J) is a multifunctional protein that reduces the aggregation and toxicity of Aβ and appears to be beneficial in atherosclerosis (26)(27). We recently demonstrated that in APP/PS1 mouse models of Alzheimer’s disease, crossed with clusterin knockout mice, result in disappearance of Aβ plaques but an increase in severity of CAA. These findings suggest that clusterin is required for efficient chaperoning of solubilized proteins from plaques along IPAD (28). Administration of clusterin as a preventative therapy when the integrity and function of smooth muscle cells and basement membranes are not compromised may yield positive results for the prevention or delay in onset of symptoms of CAA and Alzheimer’s disease. Taxifolin is flavonoid that appears to maintain amyloid in its soluble forms more amenable for clearance (29) We are investigating whether Taxifolin facilitates IPAD.

 

Agents acting upon the innervation of smooth muscle cells

Experimental work is ongoing in this area. Results suggest that agents such as Prazosin, an alpha(1)-adrenoceptor antagonist, acting upon cholinergic or adrenergic innervation of cerebral arteries result in improvements of IPAD and in reduction of CAA in transgenic mouse models of Alzheimer’s disease (30).

 

 

related projects
Innervation of cerebral arteries is key for maintenance of IPAD

 Maureen Gatherer

This project, funded by Alzheimer’s Research UK in collaboration with Dr Cheryl Hawkes (Open University), tests the hypothesis that loss of perivascular innervation by cholinergic neurons leads to dysfunctional regulation of vascular tone, thereby reducing the motive force for perivascular drainage of Aβ leading to a worsening of cerebral amyloid angiopathy.

Noradrenergic regulation of amyloid clearance in AD

In this project we will test the extent to which noradrenergic locus coeruleus and cholinergic basal forebrain projection system degeneration contributes to the progression of Alzeimer’s disease by disrupting the clearance of amyloid-β (Aβ) peptides from the brain via the IPAD pathway.

BrightFocus Foundation (USA) collaboration with Michigan State University
Anhydrase Inhibitors to treat Alzheimer’s Disease

Here, we will test the overarching hypothesis that carbonic anhydrase inhibitors have the potential to prevent mitochondrial and cell death pathways induced by the deposition of Aβ in IPAD pathways around smooth muscle cells, preventing/delaying cerebral amyloid angiopathy.

The Edward N. and Della L. Thome Memorial Foundation collaborative project with Dr. Silvia Fossati, Unniversity of Pennsylvania

Working in collaboration with Vaxxinity to test proprietary synthetic peptide immunogens for an active immunisation targeted at tau protein in Alzheimer’s disease.

 Dr Christopher Brown

Hyperphosphorylation of microtubule-associated tau proteins and their self-assembly into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) is a key feature in the pathogenesis of Alzheimer’s disease (AD). Tau pathology is a promising target for therapeutic intervention in AD as it appears early in life and corelates strongly with the progress of cognitive decline. Indeed, attempts to target tau pathology with antibodies directed against phosphorylated tau proteins have yielded encouraging results in mouse models of AD, demonstrating reductions in tau aggregation and improved cognitive function. Clinical trials are now underway for several tau immunotherapies, including two active immunisations and six passive immunisations that have reached Phase 2 trials in AD patients.

One of the main problems in preclinical testing of immunisation against tau is the lack of a suitable animal model. Human imaging and post-mortem studies suggest that tau misfolded protein seeds are transmitted in a prion-like manner from cell to cell and this has been demonstrated successfully in both cell cultures and mouse models. Immunisation preclinical studies show that using a tau transgenic mouse model alone is not sufficient, requiring the need for inoculation of preformed tau fibrils or, even better, the inoculation of tau extracts from human AD brains. Through a collaboration with Vaxxinity, an international drug company specialising in vaccines in neurodegenerative diseases, we are testing the ability of proprietary synthetic peptide immunogens to prevent the spread of tau pathology in mice inoculated with pathological tau extracted from post-mortem human AD brain tissue.

Investigating Immunisation Strategies for the Treatment of Synucleinopathies

 Dr Christopher Brown

Next generation immunisation strategies have enabled the manufacture of highly efficacious vaccines to treat major global diseases which are currently untreatable. United Neuroscience (UNS), a biotechnological company, has aimed to overcome the current vaccine challenges in the field of neurodegenerative disease by designing highly targeted vaccines which elicit a protective immune response. Synucleinopathies comprise a group of neurodegenerative diseases that are characterised by primary alpha-synuclein (α-Syn) pathology such as Dementia with Lewy Bodies (DLB), Parkinson’s disease (PD) and Multiple systems atrophy (MSA). The central role of α-Syn in the pathogenesis of these diseases highlights it as a promising target for therapy. In this study we aim to test the effects of novel α-Syn vaccines developed by UNS on preventing the onset and progression of neurodegeneration in mouse models of these synucleinopathies. In order to investigate this, we first need to understand the pathway along which α-Syn is naturally cleared from the brain and we can then establish how immunotherapy modulates this process and evaluate the neuroprotective effects of this as a treatment.

Stearoyl-CoA desaturase (SCD) in neurodegenerative disease

 Dr Jennifer Dewing

The enzyme stearoyl-CoA desaturase (SCD) is involved in the biosynthesis of monounsaturated fatty acids (MUFAs) and elevated mRNA levels of SCD1 and SCD5 isoforms have been detected in brains from Alzheimer’s disease patients. However, we have yet to understand why this occurs and how SCD may be involved in the development and progression of neurodegenerative diseases. In collaboration with the USA-based biotech company Yumanity, we are investigating the link between SCD and neurodegenerative disease in UK biobank tissue and testing the effect of specific drugs on SCD1 and SCD5 targets in animal models of central nervous system disease.