Dysregulation of cellular calcium homeostasis in Alzheimer's disease - Badgenes and bad habits

Calcium is one of the most important intracellular messengers in the brain, being essential for neuronal development, synaptic transmission and plasti city, and the regulation of various metabolic pathways. The findings review ed in the present article suggest that calcium also plays a prominent role in the pathogenesis of Alzheimer's disease (AD). Associations between the p athological hallmarks of AD (neurofibrillary tangles [NFT] and amyloid plaq ues) and perturbed cellular calcium homeostasis have been established in st udies of patients, and in animal and cell culture models of AD. Studies of the effects of mutations in the beta -amyloid precursor protein (APP) and p resenilins on neuronal plasticity and survival have provided insight into t he molecular cascades that result in synaptic dysfunction and neuronal dege neration in AD. Central to the neurodegenerative process is the inability o f neurons to properly regulate intracellular calcium levels. Increased leve ls of amyloid beta -peptide (A beta) induce oxidative stress, which impairs cellular ion homeostasis and energy metabolism and renders neurons vulnera ble to apoptosis and excitotoxicity. Subtoxic levels of A beta may induce s ynaptic dysfunction by impairing multiple signal transduction pathways. Pre senilin mutations perturb calcium homeostasis in the endoplasmic reticulum in a way that sensitizes neurons to apoptosis and excitotoxicity; links bet ween aberrant calcium regulation and altered APP processing are emerging. E nvironmental risk factors for AD are being identified and may include high calorie diets, folic acid insufficiency, and a low level of intellectual ac tivity (bad habits); in each case, the environmental factor impacts on neur onal calcium homeostasis. Low calorie diets and intellectual activity may g uard against AD by stimulating production of neurotrophic factors and chape rone proteins, The emerging picture of the cell and molecular biology of AD is revealing novel preventative and therapeutic strategies for eradicating this growing epidemic of the elderly.