One in three individuals reaching the age of 60 will have a stroke, develop dementia or both, unless prevention improves. Converging literature suggests that Alzheimer Disease (AD) and cerebrovascular disease not only coexist, but interact. Clinical investigations have also highlighted the critical relationship between stroke and other vascular risk factors and cognitive impairment. Stroke alters the clinical expression of a given load AD pathology and beta amyloid (Aβ) burden alters the clinical response to a stroke. Therefore it is possible that the exacerbated levels of Aβ and corresponding neuroinflammation if left untreated may fester over time and lead to enhanced neurodegeneration and cognitive decline. One such mechanism that may render neurons more or less sensitive to toxic insults may lie within the neuron’s physical structure. The plasma membrane, composed mainly of lipids is a fluid dynamic structure that has the ability to change its fatty acid composition to adjust and react to its external environment. Some of the plasma membrane’s heterogeneous function is determined by its structure through the formation of membrane raft (or lipid raft) domains. Membrane rafts are membrane microdomains that are rich in sphingolipids and cholesterol and have been shown to play a role in neuronal domain specific signaling events including axonal growth and neurodegeneration. An understanding of plasma membrane lipid biochemistry may prove to be valuable in the fight against brain disease.
Research Focus #1: Rodent models of co-morbidity:
To explore the relationship between vascular risk factors and AD, novel rodent models of neurodegenerative diseases have been and are currently being developed in the laboratory. Characterization of these models on their own, or in combination is done using standard histological, biochemical and behavioural assays. Rodent models include AD, stroke, diabetes and hypertension.
Research Focus #2: Membrane lipids and neurodegeneration:
MALDI-MS imaging is an emerging technology that combines the multichannel (m/z) measurement capability of mass spectrometers with a surface sampling process that allows rapid real-time probing and mapping of small molecule content in tissues. This is a valuable tool to investigate the spatial distribution of specific biomolecules in biological systems and animal models of disease, including components of membrane rafts. Using this technique and other biochemical methodology, we evaluate the temporal and spatial expression pattern of various membrane lipids in our rodent models of AD and stroke.
Research in our laboratory addresses two major hurdles in the understanding of co-morbid brain diseases such as AD and stroke. The first is via the development and characterization of physiologically relevant animal model systems that accurately reflect what is seen humans. The second hurdle that this proposal addresses is a common molecular target, or series of targets that can change in both AD and stroke. Studying the lipid changes within the plasma membrane is an intuitive strategy since the plasma membrane is more often than not the first sight of cellular response to stress.
S.N. Whitehead, K.H.N Chan, S. Gangaraju, J. Slinn, J. Li and S.T. Hou. Imaging Mass Spectrometry Detection of Gangliosides Species Within the Mouse Brain Following Transient Focal Cerebral Ischemia. PLoS One. 2011;6(6):e20808. Epub 2011 Jun 8.
S.N. Whitehead, S. Gangaraju, J. Slinn and S.T. Hou. Transient and bilateral increase in Neuropilin-1, Fer kinase and collapsin response mediator proteins within membrane rafts following unilateral occlusion of the middle cerebral artery in mouse. Brain Res. 2010 Jul 16;1344:209-16.
S.X. Jiang, S.N. Whitehead, A. Aylsworth, J. Slinn, B. Zurakouski, K. Chan, J. Li and S.T. Hou. Neuropilin 1 directly interacts with Fer kinase to mediate semaphorin3A-induced death of cortical neurons. J Biol Chem. 2010 Mar 26;285(13):9908-18
S.D Ryan, S.N. Whitehead, W. Hou, L. Swayne, M. Ethier, A.J.G Bourgeois, T.C. Moffat, J. Rashidian J, D. Qu, P.E. Fraser, D. Figeys, D.S. Park and S.A.L. Bennett. Aberrant lipid metabolism compromises neuronal vulnerability in Alzheimer disease. Proc Natl Acad Sci U S A. 2009 Nov 19.
S.N. Whitehead, G. Cheng, V. Hachinski and D.F. Cechetto. Progressive increase in infarct size, neuroinflammation and cognitive deficits in the presence of high levels of amyloid. Stroke. 2007 Dec;38(12):3245-50.
S.N. Whitehead, W. Hou, M. Ethier, J. Smith, R. Denis, S.A.L. Bennett and D. Figeys. Rapid identification and quantitation of changes in the platelet activating factor family of glycerophospholipids over the course of neuronal differentiation by high performance liquid chromatography electrospray ionization tandem mass spectrometry. Anal Chem. Nov 2007 15;79(22):8539-48.
S.N. Whitehead, G. Cheng, V. Hachinski and D.F. Cechetto. Interaction between a rat model of Aβ toxicity and cerebral ischemia: II. Effects of triflusal, a Cox-2 inhibitor. Stroke 2005; 36(8):1782-9.
S.N. Whitehead, V. Hachinksi and D.F. Cechetto. Interaction between a rat model of Aβ toxicity and cerebral ischemia: I. Inflammatory Responses. Stroke 2005; 36(1):107-12