Alzheimer disease

Apoptosis, a genetically programmed form of cell death that utilizes caspases, is a fundamental biological process essential for development and normal tissue homeostasis. In Alzheimer disease alterations in components of the cell death machinery occur and enhance apoptosis. Caspases post-translationally modify their substrates through cleavage at specific recognition sites and cause either inactivation of the protein or generation of fragments of the protein with novel functions compared to the parent protein. Activation of caspases and proteolytic cleavage of specific caspase substrates is an early, critical cellular event in several neurodegenerative diseases. Indeed, studies in patients, experimental animals and cell culture models of Alzheimer disease, Huntington disease and stroke provides strong evidence of potential universal mechanisms in the early stages of neurodegeneration and include an important role for caspase-6.

Human Alzheimer disease brain shows a significant increase in caspase-6 mRNA and active caspase-6 (Pompl et al., 2003). Furthermore, cleavage of caspase-6 substrates is observed early in human Alzheimer disease brain and the fragments demonstrated to be involved in the pathogenesis of the disease (Albrecht et al., 2007; Guo et al., 2004; Halawani et al., 2010). In support of this, recent studies suggest caspase activation precedes and leads to tangle formation (de Calignon et al., 2010). Caspase-6 generated fragments of amyloid precursor protein (APP) are observed early in human Alzheimer disease brain and processing of APP at this site generates a small peptide that is a potent inducer of apoptosis (Zhao et al., 2003; Lu et al., 2000). Importantly, activation of caspase-6 is observed prior to the clinical and pathological diagnosis of both Alzheimer disease and Huntington disease (Albrecht et al., 2007; Graham et al., 2010). Furthermore, prevention of caspase-6 proteolytic processing of APP and/or mutant huntingtin in Alzheimer disease and Huntington disease, respectively has been beneficial in these conditions (Graham et al., 2006; Galvan et al., 2006) making caspase-6 a potential target for therapeutic intervention.

Problem: Studies on human Alzheimer disease post mortem tissue have elucidated a clear role for caspase-6 in the pathogenesis of Alzheimer disease . However, at the present time it is unclear how caspase-6 activation leads to neuronal dysfunction and cell death in Alzheimer disease and difficulties in obtaining sufficient human tissue throughout the course of the disease preclude a natural history characterization of caspase activation pathways in human Alzheimer disease brain. Models of Alzheimer disease circumvent this and enable a detailed assessment of all aspects of neurodegeneration including delineation of important early primary events and not simply secondary effects due to cell loss. Investigation of the role of caspase-6 signaling pathways in Alzheimer disease will identify novel therapeutic approaches. Furthermore, characterization of caspase activation pathways in neuronal populations affected initially in the disease will also provide early markers of neuronal dysfunction that can then be used as biomarkers.

Websites for information on Alzheimer disease :

Alzheimer Society

http://www.alzheimer.ca/

Heart and Stroke foundation

http://www.alzheimer.ca/

Sites internet pour de l'information sur la maladie d'Alzheimer :

Société Alzheimer Estrie

http://www.alzheimerestrie.com/

Société Alzheimer du Québec

http://www.societealzheimerdequebec.com/wp/

Société Alzheimer du Canada

http://www.alzheimer.ca/fr/?gclid=CO2Vp7COs7wCFctcMgodJXEAqA