(555.4) A dual potassium channelopathy underlies small vessel disease of the brain in a mouse model of Alzheimers Disease

Poster Board Number: E64

Jade Taylor (Universiy of Manchester), Harry Pritchard (Universiy of Manchester), Katy Walsh (Universiy of Manchester), Grant Hennig (The University of Vermont), Stuart Allan (Universiy of Manchester), Mark Nelson (The University of Vermont, Universiy of Manchester), Adam Greenstein (Universiy of Manchester)

Mounting clinical and basic evidence has suggested that cerebral microcirculatory dysfunction is key to the pathogenesis of Alzheimer’s disease (AD), thus posing a potential new therapeutic target for AD treatment. However, despite observations of altered cerebral blood flow and autoregulatory capacity in AD patients, the underlying pathogenic mechanisms behind these defects are currently unknown. Here we present the first detailed study in to vascular ion channel function in the APP23 mouse model of AD. This model has a seven-fold increase in amyloid precursor protein leading to substantial amyloid-β plaque accumulation within the brain, as is described in AD patients. Using a range of physiological techniques; mainly pressure myography, patch clamp electrophysiology and high-speed spinning disc confocal microscopy, we show that attenuation of large conductance calcium–activated potassium (BK) channel function in this model, due to a reduced frequency of calcium sparks, is responsible for the reduction in cerebral blood flow described. Further investigation into the role of amyloid-β 1-40, in particular, showed that vessels exposed to the peptide for 30 minutes exhibited significantly reduced BK channel function at both the cellular and vascular level. However, disparate from the APP23 mouse model, acute exposure to amyloid-β 1-40 resulted in an increase in calcium waves. Both a decrease in calcium sparks (as seen in the APP23 model) and an increase in calcium waves (as seen with acute application of the amyloid-β 1-40 peptide) results in contraction of cerebral arteries and a subsequent reduction of cerebral blood flow. The data directs future research in to preventative strategies that may help to stop alterations in calcium event initiation, restore microvasculature function and promote a healthy brain environment to limit disease progression in AD patients. 

Support or Funding Information

ARUK Fellowship, Bonham Carter Family Scholarship, British Heart Foundation, Saudi Arabia Ministry for Education Scholarship Fund, Fondation Leducq.