Mitochondrial Dysfunctions in Neurodegenerative Diseases: Relevance to Alzheimer’s Disease

Table 1

Evidences of ETC dysfunctions in AD.

Biological model	Affected mitochondrial function	Reference
Lymphocyte mitochondria of AD patients	Higher oxidative (oxidation of pyruvate-malate, glycerol-3-phosphate) and enzymatic activities (I, II, and III) were found in AD patients treated with rivastigmine rather than untreated AD patients.	[81]
Transgenic mice crude forebrain	Tau-dependent deregulation of complex I and Aβ-dependent deregulation of complex II, synergistic effects of deregulation in AD mice, and reduction in mitochondrial membrane potential.	[82]
Lymphocytes	Alterations in respiratory chains—activity of complexes II and IV was higher.	[74]
Platelets and postmortem motor cortex and hippocampus from AD patients	COX but not F0F1-ATPase is a mitochondrial target in AD, in both a brain association area and platelets. A reduced COX activity may make the tissue vulnerable to excitotoxicity or reduced oxygen availability.	[83]
Posterior cingulate (area 23) cortex	The findings suggest a decrement of cytochrome oxidase in posterior cingulate cortex, with progressive reduction within the superficial laminas linked to disease duration.	[84]
Platelet and lymphocyte mitochondria	Significant declines in complexes III and IV.	[71]
Postmortem brain tissue	Complex I and complexes II-III slightly decreased in occipital cortex, and COX decreased significantly in cortical areas (frontal, temporal, parietal, and occipital).	[69]
Autopsied human brain mitochondria	AD brain mitochondria demonstrated a generalized depression of activity of all electron transport chain complexes. This depression was most marked in COX activity (𝑃<0.001). Concentrations of cytochromes b, c1, and aa3 were similar in AD and controls. The electron transport chain is defective in AD brain, and the defect centers around COX.	[61]
Subcortical centers: thalamus, the globus pallidus, the red nucleus, and the locus coeruleus	Changes of the mitochondrial cristae, accumulation of osmiophilic material and decrease of their size, and mitochondrial alterations were particularly prominent in neurons, which showed loss of dendritic spines and abbreviation of the dendritic arborization.	[85]
Human seven brain regions (cerebellum, frontal, temporal, occipital, parietal cortices, thalamus, and caudate nucleus)	Complex III core protein was significantly reduced in the temporal cortex of AD patients.	[86]
Autopsied brain mitochondria	COX activity reduced in frontal, temporal, and parietal cortices and normal COX activity reduced in occipital cortex.	[87]
Human seven brain regions (cerebellum, frontal, temporal, occipital, parietal cortices, thalamus, and caudate nucleus)	Complex I 24-kDa subunit was significantly reduced in temporal and occipital cortices. Complex I 75-kDa subunit was significantly reduced in parietal cortex region of brain.	[88]
Human brain: frontal cortex, temporal cortex, hippocampus, and cerebellum	Specific defect of COX in the confined brain regions, suggesting anatomic specificity.	[70]
Human cytoplasmic hybrid (cybrid) neurons with incorporated platelet mitochondria	Significant changes in morphology and function; such changes associate with altered expression and distribution of dynamin-like protein (Dlp1) and mitofusin 2 (Mfn2), mitochondrial fission-fusion imbalances.	[89]
In situ nerve terminal and synaptosomal mitochondria of rats	High level of inhibition is required for glutamate efflux from nerve terminal.	[77]
Rat forebrain mitochondria	Loss of cyt c by mitochondria oxidizing NAD^+-linked substrates results in a dramatic increase of ROS production and respiratory inhibition.	[90]
Mitochondria from brains of transgenic mice	Aβ progressively accumulates in mitochondria and is associated with diminished enzymatic activity of complex III and COX, reduction in the rate of oxygen consumption.	[91]
Human neuroblastoma cells (SH-SY5Y)	Increased complex III activity and decreased COX activity were found.; Decreased respiratory control ratio and ATP levels.	[39]
Human blood platelets	ATP levels were reduced, while ROS were increased in AD patients. Platelet membrane fluidity, vitamin E, and cholesterol content were similar between effected and noneffected groups.	[92]