Widespread γ-secretase activity in the cell, but do we need it at the mitochondria?

γ-Secretase cleavage of the amyloid precursor protein already subjected to a prior β-secretase cleavage generates β-amyloid (Aβ) peptide fragments, which are major constituents of the amyloid plagues found in Alzheimer's disease brain tissues. γ-Secretase activity and components of the γ-secretase complex are found in the endoplasmic reticulum-Golgi intermediate compartment, the Golgi, the trans-Golgi network, the plasma membrane, the endosomal-lysosomal system and recently, the mitochondria. Aβ fragments have been shown to be neurotoxic, leading to mitochondrial dysfunction and enhanced apoptotic cell death. However, if Aβ fragments are indeed detrimental to neurons, the widespread presence of enzymatic activity that would result in their generation in the cell appears to make little sense. The presence of a γ-secretase complex in the mitochondrion, an organelle that is particularly susceptible to Aβ toxicity, is even more puzzling. Emerging evidence suggests that both secreted and intracellular Aβ fragments have endogenous functions. Also, while the fibrillogenic Aβ1-42 is clearly neurotoxic, the more abundant and soluble Aβ1-40 is an antioxidant and could potentially be neuroprotective in several ways. A “physiological” amount of Aβ1-40 production by cellular γ-secretase activity may be part of the neuron's natural counter against oxidative damage, in addition to endogenous roles in neuronal survival and modulation of synaptic transmission. In any case, whether Aβ is produced locally in the mitochondria and the function for mitochondrial Aβ, if produced, is yet unclear.