Alzheimer's Disease Mitochondria Research Articles

OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.

Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/ PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.

Mitochondrial Targeting against Alzheimer's Disease: Lessons from Hibernation.

Alzheimer's disease (AD) is the most common cause of dementia worldwide and yet remains without effective therapy. Amongst the many proposed causes of AD, the mitochondrial cascade hypothesis is gaining attention. Accumulating evidence shows that mitochondrial dysfunction is a driving force behind synaptic dysfunction and cognitive decline in AD patients. However, therapies targeting the mitochondria in AD have proven unsuccessful so far, and out-of-the-box options, such as hibernation-derived mitochondrial mechanisms, may provide valuable new insights. Hibernators uniquely and rapidly alternate between suppression and re-activation of the mitochondria while maintaining a sufficient energy supply and without acquiring ROS damage. Here, we briefly give an overview of mitochondrial dysfunction in AD, how it affects synaptic function, and why mitochondrial targeting in AD has remained unsuccessful so far. We then discuss mitochondria in hibernation and daily torpor in mice, covering current advancements in hibernation-derived mitochondrial targeting strategies. We conclude with new ideas on how hibernation-derived dual mitochondrial targeting of both the ATP and ROS pathways may boost mitochondrial health and induce local synaptic protein translation to increase synaptic function and plasticity. Further exploration of these mechanisms may provide more effective treatment options for AD in the future.

Upregulation of Wnt2b exerts neuroprotective effect by alleviating mitochondrial dysfunction in Alzheimer's disease.

This study investigated the relationship between plasma Wnt2b levels and Alzheimer's disease (AD), and explored the effect of Wnt2b on mitochondrial dysfunction in AD. Healthy and AD subjects, AD transgenic mice, and in vitro models were used to investigate the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT-qPCR, immunoblotting, and immunofluorescence analysis were performed to assay canonical Wnt signaling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis. Plasma Wnt2b levels were lower in AD patients and positively correlated with cognitive performance. Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models. Next, Wnt2b overexpression and recombinant Wnt2b were used to endogenously and exogenously upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated. Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and upregulation of Wnt2b can exert neuroprotective effects in AD, particularly in ameliorating mitochondrial dysfunction.

Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease.

IntroductionFindings regarding the association between mitochondrial DNA (mtDNA) variants and Alzheimer's disease (AD) are inconsistent.MethodsWe developed a pipeline for accurate assembly and variant calling in mitochondrial genomes embedded within whole exome sequences (WES) from 10,831 participants from the Alzheimer's Disease Sequencing Project (ADSP). Association of AD risk was evaluated with each mtDNA variant and variants located in 1158 nuclear genes related to mitochondrial function using the SCORE test. Gene‐based tests were performed using SKAT‐O.ResultsAnalysis of 4220 mtDNA variants revealed study‐wide significant association of AD with a rare MT‐ND4L variant (rs28709356 C>T; minor allele frequency = 0.002; P = 7.3 × 10−5) as well as with MT‐ND4L in a gene‐based test (P = 6.71 × 10−5). Significant association was also observed with a MT‐related nuclear gene, TAMM41, in a gene‐based test (P = 2.7 × 10−5). The expression of TAMM41 was lower in AD cases than controls (P = .00046) or mild cognitive impairment cases (P = .03).DiscussionSignificant findings in MT‐ND4L and TAMM41 provide evidence for a role of mitochondria in AD.

Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease.

Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). A major source of free radicals that lead to oxidative and nitrosative damage is mitochondria. This review paper discusses oxidative and nitrosative stress and markers thereof in the brain, along with redox proteomics, which are techniques that have been pioneered in the Butterfield laboratory. Selected biological alterations in—and oxidative and nitrosative modifications of—mitochondria in AD and MCI and systems of relevance thereof also are presented. The review article concludes with a section on the implications of mitochondrial oxidative and nitrosative stress in MCI and AD with respect to imaging studies in and targeted therapies toward these disorders. Taken together, this review provides support for the notion that brain mitochondrial alterations in AD and MCI are key components of oxidative and nitrosative stress observed in these two disorders, and as such, they provide potentially promising therapeutic targets to slow—and hopefully one day stop—the progression of AD, which is a devastating dementing disorder.

Mitochondrial Cholesterol in Alzheimer's Disease and Niemann-Pick Type C Disease.

Mitochondrial dysfunction has been recognized as a key player in neurodegenerative diseases, including Alzheimer's disease (AD) and Niemann–Pick type C (NPC) disease. While the pathogenesis of both diseases is different, disruption of intracellular cholesterol trafficking has emerged as a common feature of both AD and NPC disease. Nutritional or genetic mitochondrial cholesterol accumulation sensitizes neurons to Aβ-mediated neurotoxicity in vitro and promotes cognitive decline in AD models. In addition to the primary accumulation of cholesterol and sphingolipids in lysosomes, NPC disease is also characterized by an increase in mitochondrial cholesterol levels in affected organs, predominantly in brain and liver. In both diseases, mitochondrial cholesterol accumulation disrupts membrane physical properties and restricts the transport of glutathione into mitochondrial matrix, thus impairing the mitochondrial antioxidant defense strategy. The underlying mechanisms leading to mitochondrial cholesterol accumulation in AD and NPC diseases are not fully understood. In the present manuscript, we discuss evidence for the potential role of StARD1 in promoting the trafficking of cholesterol to mitochondria in AD and NPC, whose upregulation involves an endoplasmic reticulum stress and a decrease in acid ceramidase expression, respectively. These findings imply that targeting StARD1 or boosting the mitochondrial antioxidant defense may emerge as a promising approach for both AD and NPC disease.

Mitochondria and Alzheimer’s: Is PTCD1 the Smoking Gun?

Multiple features distinguish the mitochondria of Alzheimer's disease (AD) patients from those of unaffected individuals. The causes and consequences of these differences are informed by the recent finding by Fleck etal. (J.Neurosci., 2019) that pentatricopeptide repeat-containing protein 1 (PTCD1) gene variants associate with AD. This suggests a proximal or initiating role for mitochondria in AD.

Targeting Mitochondria in Alzheimer Disease: Rationale and Perspectives.

A decline in mitochondrial function plays a key role in the aging process and increases the incidence of age-related disorders, including Alzheimer disease (AD). Mitochondria-the power station of the organism-can affect several different cellular activities, including abnormal cellular energy generation, response to toxic insults, regulation of metabolism, and execution of cell death. In AD subjects, mitochondria are characterized by impaired function such as lowered oxidative phosphorylation, decreased adenosine triphosphate production, significant increased reactive oxygen species generation, and compromised antioxidant defense. The current review discusses the most relevant mitochondrial defects that are considered to play a significant role in AD and that may offer promising therapeutic targets for the treatment/prevention of AD. In addition, we discuss mechanisms of action and translational potential of some promising mitochondrial and bioenergetic therapeutics for AD including compounds able to potentiate energy production, antioxidants to scavenge reactive oxygen species and reduce oxidative damage, glucose metabolism, and candidates that target mitophagy. While mitochondrial therapeutic strategies have shown promise at the preclinical stage, there has been little progress in clinical trials. Thus, there is an urgent need to better understand the mechanisms regulating mitochondrial homeostasis in order to identify powerful drug candidates that target 'in and out' the mitochondria to preserve cognitive functions.

Dysfunctional Mitochondrial Bioenergetics and Synaptic Degeneration in Alzheimer Disease.

Synapses are sites of high energy demand which are dependent on high levels of mitochondrial derived adenosine triphosphate. Mitochondria within synaptic structures are key for maintenance of functional neurotransmission and this critical biological process is modulated by energy metabolism, mitochondrial distribution, mitochondrial trafficking, and cellular synaptic calcium flux. Synapse loss is presumed to be an early yet progressive pathological event in Alzheimer disease (AD), resulting in impaired cognitive function and memory loss which is particularly prevalent at later stages of disease. Supporting evidence from AD patients and animal models suggests that pathological mitochondrial dynamics indeed occurs early and is highly associated with synaptic lesions and degeneration in AD neurons. This review comprehensively highlights recent findings that describe how synaptic mitochondria pathology involves dysfunctional trafficking of this organelle, to maladaptive epigenetic contributions affecting mitochondrial function in AD. We further discuss how these negative, dynamic alterations impact synaptic function associated with AD. Finally, this review explores how antioxidant therapeutic approaches targeting mitochondria in AD can further clinical research and basic science investigations to advance our in-depth understanding of the pathogenesis of AD.

MTDNA HAPLOGROUP ASSOCIATIONS WITH ALZHEIMER’S DISEASE RISK

Extensive research ties mitochondria to Alzheimer's disease (AD), but how mitochondria contribute to AD risk or progression remains unsettled. If other pathologies primarily perturb mitochondria in AD, downstream mitochondrial changes could represent inconsequential biomarkers of or perhaps mediate the effects of the responsible upstream pathologies. Alternatively, mitochondria may independently contribute to AD. We generated complete mtDNA sequences from 150 AD and 297 control subjects from the KU ADC clinical cohort. For a replication cohort we considered publically available ADNI mtDNA haplogroup data (191 AD, 279 control). In the KU ADC cohort, the haplogroup J frequency was significantly increased in those with AD (16.0% vs 7.4%; p=0.008), with an odds ratio (OR) of 2.38, lower confidence interval (LCI) of 1.29, and upper confidence interval (UCI) of 4.39. Four J-defining variants appeared to mediate this association (C295T, T489C, C16069T, G13708A). We also observed that the haplogroup K frequency was lower in those with AD (4.7% vs 11.1%; p=0.023), with an OR of 0.39, LCI of 0.17, and UCI of 0.90. A haplogroup K pre-variant, the synonymous T9698C transition, additionally associated with lower AD risk (p=0.039). The ADNI cohort similarly showed a significant increase in haplogroup J in AD participants (12.6% vs 6.5%; p=0.031), with an OR of 2.084, LCI of 1.10, and UCI of 3.93. ADNI AD and control haplogroup K frequencies were comparable. Detailed haplogroup analysis based on mtDNA deep sequencing indicates inherited mtDNA haplogroup variants associate with AD, which argues mitochondria independently contribute to AD. Further analysis to determine if other factors mediate observed mtDNA-AD associations is indicated.

Mechanisms of Mitochondrial Dysfunction in Alzheimer’s Disease

Mitochondria are the primary source for energy generation in the cell, which manifests itself in the form of the adenosine triphosphate (ATP). Nicotinamide dinucleotide (NADH) molecules are the first to enter the so-called electron transport chain or ETC of the mitochondria. The ETC represents a chain of reducing agents organized into four major protein-metal complexes (I-IV) that utilize the flow of electrons to drive the production of ATP. An additional integral protein that is related to oxidative phosphorylation is ATP synthase, referred to as complex V. Complex V carries out ATP synthesis as a result of the electron flow through the ETC. The coupling of electron flow from NADH to molecular oxygen to the production of ATP represents a process known as oxidative phosphorylation. In this review, we describe mainly the bioenergetic properties of mitochondria, such as those found in the ETC that may be altered in Alzheimer's disease (AD). Increasing evidence points to several mitochondrial functions that are affected in AD. Furthermore, it is becoming apparent that mitochondria are a potential target for treatment in early-stage AD. With growing interest in the mitochondria as a target for AD, it has been hypothesized that deficit in this organelle may be at the heart of the progression of AD itself. The role of mitochondria in AD may be significant and is emerging as a main area of AD research.

Endoplasmic Reticulum Stress Mediates Amyloid β Neurotoxicity via Mitochondrial Cholesterol Trafficking

Disrupted cholesterol homeostasis has been reported in Alzheimer disease and is thought to contribute to disease progression by promoting amyloid β (Aβ) accumulation. In particular, mitochondrial cholesterol enrichment has been shown to sensitize to Aβ-induced neurotoxicity. However, the molecular mechanisms responsible for the increased cholesterol levels and its trafficking to mitochondria in Alzheimer disease remain poorly understood. Here, we show that endoplasmic reticulum (ER) stress triggered by Aβ promotes cholesterol synthesis and mitochondrial cholesterol influx, resulting in mitochondrial glutathione (mGSH) depletion in older age amyloid precursor protein/presenilin-1 (APP/PS1) mice. Mitochondrial cholesterol accumulation was associated with increased expression of mitochondrial-associated ER membrane proteins, which favor cholesterol translocation from ER to mitochondria along with specific cholesterol carriers, particularly the steroidogenic acute regulatory protein. In vivo treatment with the ER stress inhibitor 4-phenylbutyric acid prevented mitochondrial cholesterol loading and mGSH depletion, thereby protecting APP/PS1 mice against Aβ-induced neurotoxicity. Similar protection was observed with GSH ethyl ester administration, which replenishes mGSH without affecting the unfolded protein response, thus positioning mGSH depletion downstream of ER stress. Overall, these results indicate that Aβ-mediated ER stress and increased mitochondrial cholesterol trafficking contribute to the pathologic progression observed in old APP/PS1 mice, and that ER stress inhibitors may be explored as therapeutic agents for Alzheimer disease.

Therapeutic approaches to remedy deficits in glucose metabolism and mitochondria

Many abnormalities in mitochondria and glucose metabolism have been reported in Alzheimer's Disease (AD).A critical role of mitochondria in AD is supported by direct genetic linkage in some forms of AD (e.g., TFAM). Together these data suggest that glucose metabolism and abnormal mitochondria are valid therapeutic targets in AD. Multiple therapeutic strategies have been developed to treat mitochondrial disorders in other diseases including neurodegenerative diseases and stroke. Similar strategies for developing therapies may be beneficial in AD. Multiple in vitro approaches have been used to determine mechanism, especially transcriptional mechanism, and develop therapeutic strategies. Numerous tactics have been validated in transgenic mice. Some of the approaches have been tested in other neurodegenerative diseases including Parkinson's and Huntington's disease. Multiple in vitro approaches have been used to determine mechanism, especially transcriptional mechanism, and develop therapeutic strategies. Numerous tactics have been validated in transgenic mice. Some of the approaches have been tested in other neurodegenerative diseases including Parkinson's and Huntington's disease. Multiple strategies are available for treating abnormalities in glucose utilization and mitochondria. These strategies need to be tested in models of Alzheimer's disease neurodegenerative disorders.

Interaction between NH2-tau fragment and Aβ in Alzheimer's disease mitochondria contributes to the synaptic deterioration

Although amyloid beta (Aβ) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH2)-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)—but not the physiological full-length protein—preferentially interacts with Aβ peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides—Aβ 1–42 and the smaller and more potent NH2-26-44 peptide of the longest 20–22 kDa NH2-tau fragment—inhibit the ANT–1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD.

Lateralization of 17Beta-Hydroxysteroid Dehydrogenase Type 10 in Hippocampi of Demented and Psychotic People

Objective: The multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 could play a role in the development of Alzheimer disease via its high-affinity binding to amyloid-β peptides and its overexpression. Methods: We evaluated the specificity of alterations in mRNA/enzyme expression levels in human right and left hippocampi. Results: We observed a trend towards right/left laterality in nondemented nonpsychotic controls; however, the degree of asymmetry was higher for mRNA when compared to enzyme expression levels. In Alzheimer disease and schizophrenia, significant shifts to left/right asymmetry were found and the changes were associated with more marked increases in mRNA/enzyme expression in the left hemisphere. On the other hand, no alterations were observed in people with multi-infarct dementia. Conclusion: Our results support studies reporting an impairment of mitochondria in Alzheimer disease or schizophrenia and a higher vulnerability of the dominant hemisphere to pathological processes. Overexpression of the enzyme could be used to distinguish Alzheimer disease from multi-infarct dementia.

Autophagocytosis of Mitochondria Is Prominent in Alzheimer Disease

Mitochondrial abnormalities are prominent in Alzheimer disease. In this study, 2 mitochondrial markers, cytochrome oxidase-1 and lipoic acid, a sulfur-containing cofactor required for the activity of several mitochondrial enzyme complexes, were compared using light and electron microscopic analyses and immunoblot assays. Both lipoic acid and cytochrome oxidase-1 immunoreactivity are increased in the cytoplasm of pyramidal neurons in Alzheimer disease compared with control cases. Of significance, lipoic acid was found to be strongly associated with granular structures, and ultrastructure analysis showed localization to mitochondria, cytosol, and, importantly, in organelles identified as autophagic vacuoles and lipofuscin in Alzheimer disease but not control cases. Cytochrome oxidase-1 immunoreactivity was limited to mitochondria and cytosol in both Alzheimer and control cases. These data suggest that mitochondria are key targets of increased autophagic degradation in Alzheimer disease. Whether increased autophagocytosis is a consequence of an increased turnover of mitochondria or whether the mitochondria in Alzheimer disease are more susceptible to autophagy remains to be resolved.

Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease.

Cell bodies of neurons at risk of death in Alzheimer disease (AD) have increased lipid peroxidation, nitration, free carbonyls, and nucleic acid oxidation. These oxidative changes are uniform among neurons and are seen whether or not the neurons display neurofibrillary tangles and, in fact, are actually reduced in the latter case. In consideration of this localization of damage, in this review, we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote neuronal oxidative damage. First, mitochondrial abnormalities might be the source of reactive oxygen species yielding perikaryal oxidative damage. The common 5-kb deletion mitochondrial (mt)DNA subtype was greatly increased in the AD cases, but only in neurons at risk. The importance of such mitochondrial abnormalities to oxidative stress was indicated by a high correlation coefficient between the extent of the mtDNA increase and RNA oxidative damage (r2 = 0.87). Nonetheless, because mitochondria in AD do not show striking oxidative damage, as one would expect if they were the direct producer of free radical species, we suspected that abnormal mitochondria supply a key reactant that, once in the cytoplasm, releases radicals. One such reactant, hydrogen peroxide, (H2O2), abundant in mitochondria, can react with iron via the Fenton reaction to produce.OH. To demonstrate this directly using a modified cytochemical technique that relies on the formation of mixed valence iron complexes, we found that redox-active iron is associated with vulnerable neurons. Interestingly, removal of iron was completely affected by using deferroxamine, after which iron could be rebound to re-establish lesion-dependent catalytic redox reactivity. Characterization of the iron-binding site suggests that binding is dependent on available histidine residues and on protein conformation. Taken together with our previous studies showing abnormalities in the iron homeostatic system including heme oxygenase, iron regulatory proteins 1 and 2, ceruloplasmin, and dimethylargininase, our results indicate that iron misregulation could play an important role in the pathogenesis of AD and therefore chelation therapy may be a useful therapeutic approach. Finally, we wanted to determine the proximal cause of mitochondrial abnormalities. One interesting mechanisms involves re-entry into the cell cycle, at which point organellokinesis and proliferation results in increased mitochondria. Supporting this, we have considerable in vivo and in vitro evidence for mitotic disturbances in AD and its relationship with the pathogenesis of AD.