This is partially due to either accumulated damage to mitochondrial DNA or direct harmful effects of oxidative stress and/or A?? on mitochondrial components. Also, mitochondrial trafficking as well as mitochondrial fusion/fission selleckbio are known to be altered in AD, compromising normal neurophysiology and a healthy cellular mitochondrial pool, which eventually leads to apoptosis. Specifically, the mitochondrial impairment integrates the close interplay of the two common hallmarks of AD, plaques and NFTs, or A?? and tau, which act independently as well as synergistically on this vital organelle. With regards to the involvement of AD-related proteins in pathogenesis, a vicious cycle as well as several vicious circles within the cycle, each accelerating the other, can be drawn, emphasizing the potency of the synergistic destruction in mitochondria.

Finally, the key role of mitochondrial dysfunction in the early pathogenic pathways by which A?? leads to neuronal dysfunction in AD is particularly challenging with respect to establishing therapeutic treatments. Besides the modulation and/or removal of both A?? and tau pathology, strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function or by interfering with energy metabolism appear to be promising; these efforts also emphasize the importance of mitochondria in the pathogenesis of AD. Cellular models for AD as well as transgenic mice, and particularly triple transgenic models that combine both pathologies, are valuable tools in monitoring therapeutic interventions at the mitochondrial level.

Eventually, this may lead to therapies that prevent the progression of A?? deposits and tau hyper-phosphorylation at an early stage of disease. Abbreviations A??: amyloid-??; ABAD: A??-binding alcohol dehydrogenase; AD: Alzheimer’s disease; APP: amyloid precursor protein; APPSw: Swedish amyloid precursor protein; APPwt: wild-type amyloid precursor protein; ??KGDH: ??-ketoglutarate dehydrogenase complex; COX: cytochrome c oxidase; CypD: cyclophilin D; DLP1: dynamin-like protein 1; GSK: glycogen synthase kinase; HA: human amylin; NFT: neurofibrillary tangle; PDH: pyruvate dehydrogenase; PMRS: plasma membrane redox system; ROS: reactive Drug_discovery oxygen species; SOD: superoxide dismutase. Competing interests The authors declare that they have no competing interests.

Human thinking depends, ultimately, on the integrity of brain cell selleck inhibitor to brain cell communication. Any process that impairs this communication – whether it is congenital or acquired, static or degenerative, anatomic or metabolic – has devastating consequences for the health and well-being of that person. People with intellectual disabilities endure socioeconomic and health disparities as a consequence of their cognitive impairment [1].