Portal to Alzheimer's disease

Abstract

Genetic inactivation of the mitochondrial self-destruction mechanism improves cognition in a mouse model of Alzheimer’s disease (pages 1097–1105).

Figure 1

Mitochondria in Alzheimer’s disease. In nondiseased neurons, the mPTP is closed, and mitochondria produce ATP and maintain other functions. Cytosolic calcium levels are kept low via ATP-dependent sequestration into endoplasmic reticulum (ER), ATP-dependent extrusion through the Ca²⁺-ATPase of the plasma membrane (not shown) and energy-dependent sequestration into mitochondria. However, in neurons affected with Alzheimer’s disease, an accumulation of soluble Aβ results in elevated cytosolic calcium levels owing to leaks from Aβ-modified calcium-conducting channels in the ER and plasma membrane. Elevated cytosolic calcium may result in calcium overload of mitochondria. An accumulation of Aβ in mitochondria and its direct interaction with CypD promotes calcium-induced mPTP opening, which damages mitochondrial ultrastructure, inhibits mitochondrial ATP production and other energy-dependent functions, and releases calcium stored in mitochondria, thereby further deregulating neuronal calcium signaling. Finally, an energy deficit and a release of proapoptotic proteins from damaged mitochondria results in neuronal injury.