Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer's Disease
Torres, Angie K.
Universidad San Sebastian
Jara, Claudia
Universidad San Sebastian
Park-Kang, Han S.
Universidad San Sebastian
Polanco, Catalina M.
Universidad San Sebastian
Tapia, Diego
Universidad San Sebastian
Alarcon, Fabian
Universidad San Sebastian
de la Pena, Adely
Universidad San Sebastian
Llanquinao, Jesus
Universidad San Sebastian
Vargas-Mardones, Gabriela
Universidad San Sebastian
Indo, Javiera A.
Universidad San Sebastian
Tapia-Rojas, Cheril
Universidad San Sebastian
Journal
Journal of Alzheimer'S Disease
ISSN
1387-2877
1875-8908
Open Access
closed
Volume
84
Start page
1391
End page
1414
Alzheimer's disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-beta (A beta) peptide. The amyloid hypothesis proposes that A beta accumulation is primarily responsible for the neurotoxicity in AD. Multiple A beta-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes A beta accumulation or if is a consequence of it. A beta promotes mitochondrial failure. However, amyloid beta precursor protein (A beta PP) could be cleaved in the mitochondria producing A beta peptide. Mitochondrial-produced A beta could interact with newly formed ones or with A beta that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for A beta toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset.