Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity

With the increasing average lifespan of humans, Alzheimer's disease (AD) is the most common neurodegenerative disorder among elderly individuals. It accounts for up to 80% of all dementia cases and ranks as the fourth leading cause of death amongst those above 65 years of age [1]. Although the hallmark lesions of the disease were already described by Alois Alzheimer in 1906 - amyloid-β (Aβ)-containing plaques and microtubule-associated protein tau-containing neurofibrillary tangles (NFTs) - the underlying molecular mechanisms that cause the formation of these end-stage lesions are not known [2]. Moreover, as only a small fraction of AD is caused by autosomal dominant mutations, this comes down to a question of what is causing the prevalent sporadic cases in the first place. A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD [3-9]. Is oxidative stress accelerating the NFT and Aβ pathologies, are these lesions causing oxidative stress themselves, or are there other mechanisms involved? Within the past few years, several cell culture models as well as single, double and, more recently, triple transgenic mouse models have been developed that reproduce diverse aspects of AD. These models help in understanding the pathogenic mechanisms that lead to mitochondrial failure in AD, and in particular the interplay of AD-related cellular modifications within this process [10].Mitochondria play a pivotal role in cell survival and death by regulating both energy metabolism and apoptotic pathways (Figure 1); they contribute to many cellular functions, including intracellular calcium homeostasis, the alteration of the cellular reduction-oxidation potential, cell cycle regulation and synaptic plasticity [11]. They are the 'powerhouses of cells', providing energy via ATP generation, which is accomplished throug