Table 2.

Mitochondrial dysfunctions in AD.

Experiment models	Mitochondria dysfunctions	Mechanisms	Ref.
ApoE KO mice; Aβ1-40	Oxidative stress, mitochondrial dysfunction and caspase activation are up-regulated.	Thiobarbituric acid-reactive substances were at a higher level, which is in accordance with the situation of ApoE KO mice synapses occurred to lipid peroxidation.	[161]
Tg2576 mice	Mitochondrial stress response; altered the respiratory chain complexes I and III's protein subunit; down-regulated the state 3 respiration and noncontinuous brain mitochondria respiration; reduced glucose metabolism.	The changes in mitochondrial proteome and function in Tg2576 mice brain precede plaque pathology.	[162]
Tg mice	Synaptic mitochondria accumulate the Aβ; mitochondrial alterations; up-regulate the transform of mitochondrial permeability up-regulate the mitochondrial oxidative stress; down-regulate the ECT function and the COX activity;	Synaptic mitochondria rich in Aβ would rather have Aβ-induced damage, and synaptic mitochondrial dysfunction is linked with the development of synaptic degeneration in AD.	[91]
Overexpressing ABAD Tg mice	Neuronal oxidative stress damage and memory loss.	The active site used to inhibit NAD binding has a substantial deformation shown in the crystal structure of Aβ-bound ABAD. ABAD peptide specifically prevents ABAD-Aβ from interaction and further restraints apoptosis triggered by Aβ and neuron free-radical generation.	[163]
CypD-deficient mAPP mice	Cortical mitochondria lack of CypD leads to having immunity in mitochondrial swelling and permeability transition induced by Aβ and Ca2+.	The synaptic function can be improved by CypD deficiency.	[164]
CypD-deficient mAPP mice	Down-regulated calcium caused by mitochondrial swelling; up-regulated the uptake ability of mitochondrial calcium; improved mitochondrial respiratory function.	Neuronal and synaptic stress that CypD mediated mPTP can be triggered by mAPP and oxidative stress.	[165]
CypD-deficient mice (primary cortical neurons and astrocytes)	The reason for synaptic versus nonsynaptic mitochondria has a difference in the Ca2+ handling is that in synaptic mitochondria, the levels of CypD are detected higher.	The neuronal mitochondria had a high level of CypD makes it vulnerable to mPTP.	[166]
Tg mAPP/ABAD mice	Spontaneous generation of hydrogen peroxide and superoxide anion, and decreased ATP, the release of cytochrome c from mitochondria and induction of caspase-3-like activity followed by DNA fragmentation and loss of cell viability.	ABAD-induced oxidant stress is related to cellular dysfunction accociated with AD.	[167]
Hippocampal neurons from embryonic day 18 rats; Aβ35-25	Impaired mitochondrial transport; morphological changes; inhibited mitochondrial transport by acting through GSK3β.	To determine the important acute effect of Aβ molecules on nerve cells, which may lead to various abnormalities of neuronal function under AD conditions.	[168]
Human neuroblastoma M17 cells	Abnormal mitochondrial distribution pattern; reduced mitochondrial density.	The overexpression of DLP1 may be through the process of repopulating neurons with mitochondria to prevent ADDL-induced synapse loss, indicating that abnormal mitochondrial dynamics are fragile for the synaptic abnormal induced by ADDL.	[169]
Human neuroblastoma M17 cells (APP overexpression)	The perinuclear area is surrounded by fragmented structure and abnormal distribution; upgraded ROS levels, decreased mitochondrial potential difference, and reduced ATP releasement.	Fragmented mitochondria and abnormal distribution account for the mitochondrial and neuronal loss.	[170]
sAD patients’ fibroblasts	The characteristic of abnormal mitochondrial distribution is that slender mitochondria accumulate in the pernuclear area of 19.3% of sporadic AD (sAD) fibroblasts; decreased DLP1.	The reason why the levels of DLP1 reduced and mitochondrial allocation is unusual is that up-regulated oxidative stress and amyloid production in AD cells.	[171]
AD postmortem brain tissues, AβPP tg mice (primary hippocampal neurons)	Abnormal mitochondrial dynamics increase as AD progresses.	Crucial factors, including the increased production of Aβ and the interaction of Aβ with Drp1, lead to mitochondrial fragmentation, abnormal mitochondrial dynamics and synaptic damage.	[172]
Hippocampal neuron from C57BL/6day 1 pup; Aβ25-35 peptide	Less level of motile mitochondria; less average speed of motile mitochondria; decreased mitochondrial length; less synaptic immunoreactivity.	In neurons of AD models, toxic Aβ can impair mitochondrial movement, shorten the length of mitochondria, and endanger synaptic loss.	[173]
AD postmortem brain tissues; APP, APP/PS1 and 3XTg.AD mice	Elevated mitochondrial fission-linked GTPase activity.	Aβ and phosphorylated tau and Drp1 are entangled with each other, causing damage to mitochondria and synapses, which in turn leads to cognitive memory deficits.	[92]
AD postmortem brain tissues; CaMKIIα-tTA and tet-APPswe/ind mice	Enhanced mitophagy; depletion of cytosolic Parkin; reduced anterograde and increased retrograde transport of axonal mitochondria.	Chronic mitochondrial stress associated with AD under pathophysiological conditions in vitro and in vivo effectively triggers Parkin-dependent mitochondrial autophagy.	[174]
AD postmortem brain tissues; APP/PS1 mice	Down-regulated mitophagy.	Mitophagy enhancement eliminates AD-related tau hyperphosphorylation in human neuronal cells and reverses the memory impairment of genetically modified tau nematodes and mice.	[86]

mPTP: mitochondrial permeability transition pore; ABAD: amyloid protein binding of alcohol dehydrogenase; COX: cytochrome c oxidase; GSK3β: glycogen synthase kinase 3β; DLP1: dynamin-like protein; OPA1: mitochondrial dynamin-like GTPase; Mfn1/2: mitofusin 1/2; ADDLs: amyloid-β-derived diffusible ligands; Opa1: mitochondrial dynamin-like GTPase 1; TOMM40: translocase of outer mitochondrial membrane 40.