ALZHEIMERS DISEASE.ppt

ALZHEIMER’S DISEASE Erin Dancey Overview Alzheimer’s is the most common cause of dementia in adult life and is associated with the selective damage of brain regions and neural circuits critical for memory and cognition The pathogenesis of this disease is complex, and involves many molecular, cellular, and physiological pathologies The neurons in the neocortex, hippocampus, amygdala, and the basal forebrain cholinergic system are the most affected brain regions Amyloid Plaque Formation Alzheimer’s patients show numerous plaques which are composed of 4 kD Amyloid-beta (A-beta) peptides, which are derived from beta amyloid precursor proteins (APPs) APP is a membrane associated glycoprotein of 110-135 kDa that is proposed to normally behave in the brain as a cell surface signaling molecule A-beta peptides are generated in the endosomal compartment and in the endoplasmic reticulum or golgi complex by endoproteolytic cleavage of APP by Beta, alpha, and gamma secretases Presenilins Presenilin 1 (PS1) and presenilin 2 (PS2) are highly homologous 43-50 kD proteins with eight transmembrane domains Presenilin’s make crucial contributions to neurodegeneration in AD Presenilin’s are crucial components of the enzymes that work to cleave APP, and mutations in presenilins cause the production of A-beta42 and A-beta43 peptides (insoluble forms of A-beta) The production of A-beta production by processing of APP Amyloid Plaque formation About 90% of the secreted A-beta peptides formed from processing of APP are A-beta40, a soluble form of the peptide About 10% of secreted A-beta peptides are A-beta42 and A-beta43 A-beta42 and A-beta43 are highly fibrillogenic, readily aggregated, and neurotoxic Amyloid Plaque formation Alignment of several strands of A-beta show that A-beta42 and A-beta43 preferentially form networks of salt linkages and strong hydrogen bonds between ionized side chains of opposite charge which thus form the observed plaques Alignment of the sequence of the 42 resi