Affiliation:
1. Laboratory of Neurodegenerative Diseases, Facultad de Ciencias de la Salud, Instituto de Ciencias Biomedicas, Universidad Autonoma de Chile, Santiago, Chile
Abstract
Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in
the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the
synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of
tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively
impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects
against mitochondria health will contribute to the synaptic impairment and cognitive decline in AD.
Current studies suggest that mitochondrial failure induced by pathological tau forms is likely the result
of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial
mega-channel that is activated by increases in calcium and is associated with mitochondrial
stress and apoptosis. This structure is composed of different proteins, where Ciclophilin D (CypD)
is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP
contributes to Aβ pathology and oxidative stress in AD.
Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic
impairment in AD mouse models. More importantly, tau protein contributes to the physiological
regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons.
Therefore, in this paper, we will discuss evidence that suggests an important role of pathological
forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the
mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic
function present in AD.
Funder
Fondo de Ciencia y Tecnología
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology (medical),Psychiatry and Mental health,Clinical Neurology,Neurology,Pharmacology,General Medicine
Cited by
33 articles.
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