Mitochondrial Dysfunction In Alzheimer's Disease Research Articles

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.

Intraneuronal β-amyloid impaired mitochondrial proteostasis through the impact on LONP1.

Mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial proteostasis regulated by chaperones and proteases in each compartment of mitochondria is critical for mitochondrial function, and it is suspected that mitochondrial proteostasis deficits may be involved in mitochondrial dysfunction in AD. In this study, we identified LONP1, an ATP-dependent protease in the matrix, as a top Aβ42 interacting mitochondrial protein through an unbiased screening and found significantly decreased LONP1 expression and extensive mitochondrial proteostasis deficits in AD experimental models both in vitro and in vivo, as well as in the brain of AD patients. Impaired METTL3-m6A signaling contributed at least in part to Aβ42-induced LONP1 reduction. Moreover, Aβ42 interaction with LONP1 impaired the assembly and protease activity of LONP1 both in vitro and in vivo. Importantly, LONP1 knockdown caused mitochondrial proteostasis deficits and dysfunction in neurons, while restored expression of LONP1 in neurons expressing intracellular Aβ and in the brain of CRND8 APP transgenic mice rescued Aβ-induced mitochondrial deficits and cognitive deficits. These results demonstrated a critical role of LONP1 in disturbed mitochondrial proteostasis and mitochondrial dysfunction in AD and revealed a mechanism underlying intracellular Aβ42-induced mitochondrial toxicity through its impact on LONP1 and mitochondrial proteostasis.

Effects of Redox Homeostasis and Mitochondrial Damage on Alzheimer's Disease.

Bioenergetic mitochondrial dysfunction is a common feature of several diseases, including Alzheimer's disease (AD), where redox imbalance also plays an important role in terms of disease development. AD is an age-related disease and begins many years before the appearance of neurodegenerative symptoms. Intracellular tau aggregation, extracellular β-amyloid (Aβ) deposition in the brain, and even the APOE4 genotype contribute to the process of AD by impairing redox homeostasis and mitochondrial dysfunction. This review summarizes the evidence for the redox imbalance and mitochondrial dysfunction in AD and demonstrates the current therapeutic strategies related to mitochondrial maintenance.

Bezafibrate confers neuroprotection in the 5xFAD mouse model of Alzheimer's disease

Mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer's disease (AD), the most common neurodegenerative disease. Prior studies suggested impaired mitochondrial biogenesis likely contributes to mitochondrial dysfunction in AD. Bezafibrate, a peroxisome proliferator-activated receptor (PPAR) pan-agonist, has been shown to enhance mitochondrial biogenesis and increase oxidative phosphorylation capacity. In the present study, we investigated whether bezafibrate could rescue mitochondrial dysfunction and other AD-related deficits in 5xFAD mice. Bezafibrate was well tolerated by 5xFAD mice. Indeed, it rescued the expression of key mitochondrial proteins as well as mitochondrial dynamics and function in the brain of 5xFAD mice. Importantly, bezafibrate treatment led to significant improvement of cognitive/memory function in 5xFAD mice accompanied by alleviation of amyloid pathology and neuronal loss as well as reduced oxidative stress and neuroinflammation. Overall, this study suggests that bezafibrate improves mitochondrial function, mitigates neuroinflammation and improves cognitive functions in 5xFAD mice, thus supporting the notion that enhancing mitochondrial biogenesis/function is a promising therapeutic strategy for AD.

Mapping trends and hotspots of mitochondrial dysfunction in Alzheimer's disease from 2013 to 2022: a bibliometric analysis of global research.

Alzheimer's disease (AD), a prevalent neurodegenerative affliction that predominantly affects the elderly population, imposes a substantial burden on not only patients but also their families and society at large. Mitochondrial dysfunction plays an important role in its pathogenesis. In this study, we conducted a bibliometric analysis of research on mitochondrial dysfunction and AD over the past 10 years, with the aim of summarizing current research hotspots and trends in this field. On February 12, 2023, we searched for publications about mitochondrial dysfunction and AD in the Web of Science Core Collection database from 2013 to 2022. VOSview software, CiteSpace, SCImago, and RStudio were used to analyze and visualize countries, institutions, journals, keywords, and references. The number of publications on mitochondrial dysfunction and AD were on the rise until 2021 and decreased slightly in 2022. The United States ranks first in the number of publications, H-index, and intensity of international cooperation in this research. In terms of institutions, Texas Tech University in the United States has the most publications. The Journal of Alzheimer's Disease has the most publications in this field of research, while Oxidative Medicine and Cellular Longevity have the highest number of citations. Mitochondrial dysfunction is still an important direction of current research. Autophagy, mitochondrial autophagy, and neuroinflammation are new hotspots. The article from Lin MT is the most cited by analyzing references. Research on mitochondrial dysfunction in AD is gaining significant momentum as it provides a crucial research avenue for the treatment of this debilitating condition. This study sheds light on the present research trajectory concerning the molecular mechanisms underlying mitochondrial dysfunction in AD.

Trends of mitochondrial changes in AD: a bibliometric study.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive progress and memory loss, which eventually develops into dementia. It can cause personality disorders and decreased quality of life of patients. Currently, AD patients account for 60-70% of global dementia patients and the incidence rate of AD is increasing annually. AD not only causes pain to patients but also brings a heavy burden to the entire family. Studies have found that there is a connection between mitochondrial dysfunction and other biochemical changes in AD like classical neuropathological hallmarks (β-amyloid and tau protein), inflammation pathways, oxidative stress, and so on. Evidence shows that early treatment targeted directly to mitochondria could extend the lifespan of model mice and decrease the relevant neuropathological markers. Therefore, research on the mitochondrial dysfunction of AD can be of potential significance for clinical treatment. To date, few bibliometric analysis articles related to mitochondrial dysfunction of AD have been published. Bibliometric analysis refers to quantitatively analyzing certain aspects of articles like publishers, authors, and countries by using statistical and mathematical methods. Combined with statistical software, a large number of papers can be converted to visualization figures and tables, which provide vital information such as keyword hotspots and the names of contributing authors. Through the bibliometric analysis method, our study aimed to provide study trends and keyword hotpots for researchers to conduct further relevant research in this field. We used the Web of Science core collection database as a literature retrieval tool to obtain data related to mitochondrial changes in Alzheimer's disease during the last 20 years. The retrieval type was [TS = (Alzheimer's disease)] ND [TS = (mitochondrion)], ranging from January 1, 2000 to June 30, 2022. VOSviewer v1.6.18, Arcgis 10.8, and HistCite pro 2.1 were used to conduct data visualization analysis. VOSviewer v1.6.18 made relevant network visualization maps of the cooperative relationship between relevant countries, institutions, and authors (co-authorship), the frequency of different keywords appearing together (co-occurrence), and the frequency of different articles cited together (co-cited). Arcgis 10.8 created the world map of publications distribution in this field and Histcite pro 2.1 was used to count the local citation score (LCS) of references. In addition, Journal Citation Reports were used to consult the latest journal import factor and JCI quartile. As of June 30, 2022, from the Web of Science core collection, we selected 2,474 original articles in English, excluding the document types of the news items, meeting abstracts, and some articles that had little relevance to our theme. The United States acted as the leader and enjoyed a high reputation in this field. The University of California System was the institution that made the greatest contribution (3.64% with 90 papers). Most articles were published in the Journal of Alzheimer's Disease (8.21%, with 203 papers). The most frequently co-cited journal in Q1 was the Journal of Biological Chemistry (8,666 citations, TLS: 1039591). Russel H. Swerdlow (55 publications) was the most productive author and PH Reddy was the most co-cited author with 1,264 citations (TLS: 62971). The hotpots of mitochondrial dysfunction in AD were as follows: "oxidative stress," "amyloid-beta-protein," "tau," "apoptosis," "inflammation," "autophagy," "precursor protein," "endoplasmic-reticulum," "dynamics" and "mitochondrial unfolded protein response." This bibliometric analysis research will help readers rapidly identify current hotpots and milestone studies related to directions of interest in AD research.

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.

The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis.

To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease-modifying therapies. According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline. HIGHLIGHTS: The Amyloid Cascade Model does not readily account for various parameters associated with Alzheimer's disease (AD). A unified model correctly identifying the pathogenesis of AD is greatly needed to inform the development of successful therapeutics. Mitochondria play a key and central role in the maintenance of optimal neuronal and synaptic function, the core pathological feature of AD. Mitochondrial dysfunction may be the primary cause of AD, and is a promising target for new therapeutic strategies.

Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer's disease.

Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET). Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N=30; mean age±standard deviation: 71.8±7.6years) underwent magnetic resonance imaging and PET scans with [18 F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [11 C]Pittsburgh Compound-B (PiB) and [18 F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models. [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.

ATP synthase and Alzheimer's disease: putting a spin on the mitochondrial hypothesis.

It is estimated that over 44 million people across the globe have dementia, and half of these cases are believed to be Alzheimer’s disease (AD). As the proportion of the global population which is over the age 60 increases so will the number of individuals living with AD. This will result in ever-increasing demands on healthcare systems and the economy. AD can be either sporadic or familial, but both present with similar pathobiology and symptoms. Three prominent theories about the cause of AD are the amyloid, tau and mitochondrial hypotheses. The mitochondrial hypothesis focuses on mitochondrial dysfunction in AD, however little attention has been given to the potential dysfunction of the mitochondrial ATP synthase in AD. ATP synthase is a proton pump which harnesses the chemical potential energy of the proton gradient across the inner mitochondrial membrane (IMM), generated by the electron transport chain (ETC), in order to produce the cellular energy currency ATP. This review presents the evidence accumulated so far that demonstrates dysfunction of ATP synthase in AD, before highlighting two potential pharmacological interventions which may modulate ATP synthase.

Treadmill Exercise Attenuates Aβ-Induced Mitochondrial Dysfunction and Enhances Mitophagy Activity in APP/PS1 Transgenic Mice.

Mitochondrial dysfunction is a hallmark of Alzheimer's disease (AD), which may be related to mitophagy failure. Previous reports suggest that treadmill exercise protects against mitochondrial dysfunction in AD. However, few studies have investigated the relationship between mitophagy and mitochondrial adaptation caused by treadmill exercise in AD. The current study aimed to investigate whether exercise-ameliorated AD is associated with changes in mitophagy activity. Both Wild-type and APP/PS1 transgenic mice were divided into sedentary (WTC and ADC) and exercise (WTE and ADE) groups (n = 9 for each group). WTE and ADE mice were subjected to treadmill exercise for 12weeks, followed by evaluating the effect of treadmill exercise on learning and memory ability, Aβ plaques, mitochondrial Aβ peptide level, synaptic activity and mitochondrial function. Meanwhile, mitophagy-related proteins PINK1, Parkin, LC3II and P62 were measured in the hippocampal mitochondrial fractions. The results indicated that exercise not only restored learning and memory ability, but also reduced Aβ plaque area, mitochondrial Aβ peptide level, and increased levels of synaptic markers SYN and GAP43, as well as reversed mitochondrial dysfunction (defective mitochondrial ultrastructure, decreased PGC-1α, TFAM and ATP levels) in APP/PS1 transgenic mice. Moreover, exercise increased mitophagy activity as evidenced by a significant decrease in levels of P62 and PINK1 as well as an increase in levels of LC3II and Parkin in ADE mice. These findings suggest that treadmill exercise can enhance mitophagy activity in the hippocampus, which is efficient in ameliorating pathological phenotypes of APP/PS1 transgenic mice.

Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer's Disease.

Besides extracellular deposition of amyloid beta and formation of phosphorylated tau in the brains of patients with Alzheimer’s disease (AD), the pathogenesis of AD is also thought to involve mitochondrial dysfunctions and altered neurotransmission systems. However, none of these components can describe the diverse cognitive, behavioural, and psychiatric symptoms of AD without the pathologies interacting with one another. The purpose of this review is to understand the relationships between mitochondrial and neurotransmission dysfunctions in terms of (1) how mitochondrial alterations affect cholinergic and monoaminergic systems via disruption of energy metabolism, oxidative stress, and apoptosis; and (2) how different neurotransmission systems drive mitochondrial dysfunction via increasing amyloid beta internalisation, oxidative stress, disruption of mitochondrial permeabilisation, and mitochondrial trafficking. All these interactions are separately discussed in terms of neurotransmission systems. The association of mitochondrial dysfunctions with alterations in dopamine, norepinephrine, and histamine is the prospective goal in this research field. By unfolding the complex interactions surrounding mitochondrial dysfunction in AD, we can better develop potential treatments to delay, prevent, or cure this devastating disease.

A role for sodium glucose cotransporter 2 inhibitors (SGLT2is) in the treatment of Alzheimer's disease?

With the lack of success and increasing urgency for therapies capable of impacting Alzheimer's disease (AD) and its progression, there are increasing efforts to expand testing of new mechanistic hypotheses to attack the disease from different angles. Three such hypotheses are the "Mitochondrial Cascade (MC)" hypothesis, the "Endo-Lysosomal Dysfunction (ELD)" hypothesis and the "Type 3 Diabetes (T3D)" hypothesis. These hypotheses provide a rationale for new pharmacological approaches to address the mitochondrial, endo-lysosomal and metabolic dysfunction associated with AD. It is increasingly evident that there is critical interplay between the metabolic dysfunction associated with obesity/metabolic syndrome/type 2 diabetes mellitus (T2DM) and patient susceptibility to AD development. A candidate for a common mechanism linking these metabolically-driven disease states is chronically-activated mechanistic target of rapamycin (mTOR) signaling. Unrestrained chronic mTOR activation may be responsible for sustaining metabolic, lysosomal and mitochondrial dysfunction in AD, driving both the breakdown of the blood-brain barrier via endothelial cell dysfunction and hyperphosphorylation of tau and formation of amyloid plaques in the brain. It is hypothesized that sodium glucose cotransporter 2 (SGLT2) inhibition, mediated by sustained glucose loss, restores mTOR cycling through nutrient-driven, nightly periods of transient mTOR inhibition (and restoration of catabolic cellular housekeeping processes) interspersed by daily periods of transient mTOR activation (and anabolism) accompanying eating. In this way, a flexible mTOR dynamic is restored, thereby preventing or even reducing the progress of AD pathology. The first study to investigate the effect of SGLT2 inhibition in patients with AD is ongoing and focuses on the impact on energy metabolism in the brain following treatment with the SGLT2 inhibitor dapagliflozin.

Pramipexole improves mitochondrial function in aβ42 induced transgenic ad model of drosophila melanogaster

Alzheimer's disease (AD) is a common neurodegenerative disorder with typical clinical interventions characterized by loss of memory and cognitive function. Several lines of evidence strongly implicate mitochondrial dysfunction as a major causative factor in AD, although the molecular mechanisms responsible for mitochondrial dysfunction in AD are poorly understood. Pramipexole is a dopamine agonist with proven efficacy in mitochondrial mediated neuroprotective effect. Considering this property, we examined the effect of pramipexole in AD. To gain insight into the molecular mechanism responsible for the pathogenesis of AD, we have choosen UAS/GAL4 system for the development of transgenic AD flies that overexpress Aβ42 in the brain of Drosophila. The symptoms such as reduced lifespan, locomotor defects, and memory impairment, mitochondrial membrane potential, oxygen consumption of mitochondria and expression of caspase 3 along with mitogen associated protein kinases linked with AD were determined in the presence of pramipexole. Pramipexole resisted the Aβ42 induced behavioral outcomes, mitochondrial membrane potential, oxygen consumption along with expression of apoptotic factors (ERK, p38, pJNK and caspase 3). Thus the present study could be beneficial to find out the role of pramipexole in transgenic AD flies overexpressing human Aβ42.

P2‐251: SERUM ACYLCARNITINE LIPIDS AS BIOMARKERS OF PRECLINICAL ALZHEIMER'S DISEASE

There is now substantial evidence for a role of mitochondria dysfunction in Alzheimer's disease (AD) which is characterized by decreased mitochondria function and increased oxidative stress. Mitochondrial dysfunction in AD is accompanied by decreased bioenergetics reflected by reduced brain glucose utilization and the capacity to perform beta-oxidation in the brain regions that are affected early in the disease process. We hypothesized that free carnitine and acylcarnitines reflecting changes in mitochondrial lipid transport/beta-oxidation occur prior to the onset of AD. We examined serum aclycarnitines from a longitudinal cohort of cognitively healthy subjects (n = 198), a subset of whom converted to mild cognitive impairment (MCI) or AD within 2 to 3 years. Serum acylcarnitine extracts containing labelled acylcarnitines mixture were subjected to Hydrophilic Interaction Liquid Chromatography (HILIC) and mass spectrometry using a Q Exactive™ Hybrid Quadrupole-Orbitrap™ Mass spectrometer (Thermo Scientific) in a positive ion mode acquired with FTMS using scheduled parallel reaction monitoring at 17,500 resolution. We observed significant differences in the levels of medium- and very long-chain fatty acid (VLCFA)-containing acylcarnitine species in serum from control subjects relative to those who converted to MCI/AD. Several medium-chain fatty acid (MCFA)-containing acylcarnitine species were elevated in MCI/AD converters compared to controls who stayed cognitively intact. Interestingly, VLCFA containing species were decreased in MCI/AD converters compared to subjects who remained cognitively intact over 2 to 3 years. A combined panel of these acylcarnitine species had a greater than 80% accuracy for providing a correct classification of preclinical MCI/AD. These findings suggest that mitochondria related acylcarnitine abnormalities can be detected in serum of subjects with preclinical MCI/AD and could serve as biomarkers of early AD. Future studies are required to validate these findings in independent cohorts with a larger sample size to validate the use of serum acylcarnitines as predictors of preclinical AD.

Amyloid Beta and MicroRNAs in Alzheimer's Disease.

Alzheimer’s disease (AD) is a progressive mental illness characterized by memory loss and multiple cognitive impairments. In the last several decades, significant progress has been made in understanding basic biology, molecular mechanisms, and development of biomarkers and therapeutic drugs. Multiple cellular changes are implicated in the disease process including amyloid beta and phosphorylation of tau synaptic damage and mitochondrial dysfunction in AD. Among these, amyloid beta is considered a major player in the disease process. Recent advancements in molecular biology revealed that microRNAs (miRNAs) are considered potential biomarkers in AD with a focus on amyloid beta. In this article we discussed several aspects of AD including its prevalence, classifications, risk factors, and amyloid species and their accumulation in subcellular compartments. This article also discusses the discovery and biogenesis of miRNAs and their relevance to AD. Today’s research continues to add to the wealth of miRNA data that has been accumulated, however, there still lacks clear-cut understanding of the physiological relevance of miRNAs to AD. MiRNAs appear to regulate translation of gene products in AD and other human diseases. However, the mechanism of how many of these miRNAs regulate both the 5′ and 3′UTR of amyloid precursor protein (APP) processing is still being extrapolated. Hence, we still need more research on miRNAs and APP/amyloid beta formation in the progression and pathogenesis of AD.

Age-Dependent Decrease of Mitochondrial Complex II Activity in a Familial Mouse Model for Alzheimer's Disease.

Alzheimer's disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1ΔE9 mouse model from 4.5 to 14 months of age. We show an age-dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-β (Aβ) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Aβ pathology in this mouse model.

Development of GMP-1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease.

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and may play an important role in the pathogenesis of disease. It has been shown that amyloid beta peptide (Aβ) and amyloid precursor protein (APP) interact with mitochondria contributing to the mitochondrial dysfunction in AD. Prevention of abnormal protein targeting to mitochondria can protect normal mitochondrial function, increase neuronal survival and at the end, ameliorate symptoms of AD and other neurodegenerative disorders. First steps of mitochondrial protein import are coordinated by molecular chaperones Hsp70 and Hsp90 that bind to the newly synthesized mitochondria‐destined proteins and deliver them to the protein import receptors on the surface of organelle. Here, we have described the development of a novel compound named GMP‐1 that disrupts interactions between Hsp70/Hsp90 molecular chaperones and protein import receptor Tom70. GMP‐1 treatment of SH‐SY5Y cells results in decrease in mitochondria‐associated APP and protects SH‐SY5Y cells from toxic effect of Aβ1‐42 exposure. Experiments in drosophila and mice models of AD demonstrated neuroprotective effect of GMP‐1 treatment, improvement in memory and behaviour tests as well as restoration of mitochondrial function.

Protective effects of microRNA-330 on amyloid β-protein production, oxidative stress, and mitochondrial dysfunction in Alzheimer's disease by targeting VAV1 via the MAPK signaling pathway.

This study aims to explore the effect of miR-330 targeting VAV1 on amyloid β-protein (Aβ) production, oxidative stress (OS), and mitochondrial dysfunction in Alzheimer's disease (AD) mice through the MAPK signaling pathway. Putative targeted gene of miR-330 was performed by a miRNA target prediction website and dual-luciferase reporter gene assay. AD mouse model was successfully established. Fourteen C57 mice were randomized into AD and control groups. The positive protein expression rate of VAV1 was measured by immunohistochemistry. Neuron cells were assigned into control, blank, negative control (NC), miR-330 mimics, miR-330 inhibitors, siRNA-VAV1, and miR-330 inhibitors + siRNA-VAV1 groups. Expression of miR-330, VAV1, ERK1, JNK1, P38MAPK, Aβ, COX, and lipoprotein receptor-related protein-1 (LRP-1) were determined using RT-qPCR and Western blotting. Colorimetry was applied to measure the levels of OS parameters of superoxide dismutase (SOD) and malondialdehyde (MDA). Aβ production in brain tissue was detected using ELISA, while that in neuron cell was measured by radioimmunoassay. MiR-330 was down-regulated in neuron cells of AD mice and VAV1 was negatively regulated by miR-330. Compared with the control group, the positive protein expression rate of VAV1 was significantly elevated in the AD group. Overexpression of miR-330 decreased the expression of VAV1, ERK1, JNK1, P38MAPK, and Aβ, but increased the expression of COX and LRP-1. AD mice revealed elevated Aβ production and MDA with decreased SOD level. The result indicates that overexpressed miR-330 targeting VAV1 through the MAPK signaling pathway reduces Aβ production and alleviates OS and mitochondrial dysfunction in AD.

The Association of Tau With Mitochondrial Dysfunction in Alzheimer's Disease.

Increasing evidence suggests that abnormally hyperphosphorylated tau plays a vital role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction also has a recognized role in the pathophysiology of AD. In recent years, mitochondrial dysfunction has been strongly associated with tau pathology in AD. Overexpression of hyperphosphorylated and aggregated tau appears to damage the axonal transport, leading to abnormal mitochondrial distribution. In addition, pathological tau impairs mitochondrial dynamics by regulating mitochondrial fission/fusion proteins, and further causes mitochondrial dysfunction and neuronal damage. Moreover, mitochondrial dysfunction is also involved in promoting tau pathology in AD. In this article, we evaluate the relationship between phosphorylated tau and mitochondrial dysfunction in AD.