PINK1 Activation Attenuates Impaired Neuronal-Like Differentiation and Synaptogenesis and Mitochondrial Dysfunction in Alzheimer’s Disease Trans-Mitochondrial Cybrid Cells

Background: Mitochondrial dysfunction, bioenergetic deficit, and extensive oxidative stress underlie neuronal perturbation during the early stage of Alzheimer’s disease (AD). Previously, we demonstrated that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with AD pathology in AD-affected human brains and AD mice. Objective: In the present study, we highlight the essential role of PINK1 in AD-relevant mitochondrial perturbation and neuronal malfunction. Methods: Using trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells, whose mitochondria are transferred from platelets of patients with sporadic AD, we observed the effect of PINK1 in neuronal-like differentiation and synaptogenesis and mitochondrial functions. Results: In AD cybrid cells, the downregulation of PINK1 is correlated to the alterations in mitochondrial morphology and function and deficit in neuronal-like differentiation. Restoring/increasing PINK1 by lentivirus transduction of PINK1 robustly attenuate mitochondrial defects and rescue neurite-like outgrowth. Importantly, defective PINK1 kinase activity fails to reverse these detrimental effects. Mechanistically, AD cybrid cells reveal a significant decrease in PINK1-dependent phosphorylated mitofusin (Mfn) 2, a key mitochondrial membrane protein that participates in mitochondrial fusion, and an insufficient autophagic activity for clearance of dysfunctional mitochondria. Overexpression of PINK1, but not mutant PINK1 elevates phosphorylation of Mfn2 and autophagy signaling LC3-II. Accordingly, PINK1-overexpressed AD cybrids exhibit increases in mitochondrial length and density and suppressed reactive oxygen species. These results imply that activation of PINK1 protects against AD-affected mitochondrial dysfunction and impairment in neuronal maturation and differentiation. Conclusion: PINK1-mediated mitophagy is important for maintaining mitochondrial health by clearance of dysfunctional mitochondria and therefore, improves energy homeostasis in AD.

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Astrocytic transporters in Alzheimer's disease

Biochemical Journal ◽

10.1042/bcj20160505 ◽

2017 ◽

Vol 474 (3) ◽

pp. 333-355 ◽

Cited By ~ 7

Author(s):

Chris Ugbode ◽

Yuhan Hu ◽

Benjamin Whalley ◽

Chris Peers ◽

Marcus Rattray ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Neurological Diseases ◽

Current Evidence ◽

Specific Targeting ◽

Disease Modifying Therapies ◽

The Central Nervous System ◽

Disease Modifying ◽

And Function

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Microglia-Based Sex-Biased Neuropathology in Early-Stage Alzheimer’s Disease Model Mice and the Potential Pharmacologic Efficacy of Dioscin

Cells ◽

10.3390/cells10113261 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3261

Author(s):

Xiao Liu ◽

Qian Zhou ◽

Jia-He Zhang ◽

Xiaoying Wang ◽

Xiumei Gao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Disease Model ◽

Amyloid Β ◽

Brain Lesions ◽

Synaptic Dysfunction ◽

Synaptic Loss ◽

And Function ◽

The Brain

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

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Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.748388 ◽

2021 ◽

Vol 13 ◽

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Qingwei Huo ◽

Sumaiya Tabassum ◽

Jinxiang Jiang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Neuronal Morphology ◽

Therapeutic Interventions ◽

Early Event ◽

Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

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Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.617588 ◽

2021 ◽

Vol 13 ◽

Cited By ~ 1

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Li Yang

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Mitochondrial Morphology ◽

Therapeutic Approaches ◽

The Impact ◽

And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

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A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0823-2 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Ebru Ercan-Herbst ◽

Jens Ehrig ◽

David C. Schöndorf ◽

Annika Behrendt ◽

Bernd Klaus ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Temporal Cortex ◽

Brain Regions ◽

Phosphorylation Sites ◽

Post Translational Modification ◽

Post Translational Modifications ◽

Small Set ◽

Human Brains

AbstractTau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0–I, II or III–IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III–IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

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Mitochondrial Dysfunction: Different Routes to Alzheimer’s Disease Therapy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/780179 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 90

Author(s):

Pasquale Picone ◽

Domenico Nuzzo ◽

Luca Caruana ◽

Valeria Scafidi ◽

Marta Di Carlo

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Permeability Transition ◽

Mitochondrial Protein ◽

Radical Scavenging ◽

Permeability Transition ◽

Oxidation Potential ◽

Mitochondrial Functions

Mitochondria are dynamic ATP-generating organelle which contribute to many cellular functions including bioenergetics processes, intracellular calcium regulation, alteration of reduction-oxidation potential of cells, free radical scavenging, and activation of caspase mediated cell death. Mitochondrial functions can be negatively affected by amyloidβpeptide (Aβ), an important component in Alzheimer’s disease (AD) pathogenesis, and Aβcan interact with mitochondria and cause mitochondrial dysfunction. One of the most accepted hypotheses for AD onset implicates that mitochondrial dysfunction and oxidative stress are one of the primary events in the insurgence of the pathology. Here, we examine structural and functional mitochondrial changes in presence of Aβ. In particular we review data concerning Aβimport into mitochondrion and its involvement in mitochondrial oxidative stress, bioenergetics, biogenesis, trafficking, mitochondrial permeability transition pore (mPTP) formation, and mitochondrial protein interaction. Moreover, the development of AD therapy targeting mitochondria is also discussed.

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TOMM40 RNA Transcription in Alzheimer’s Disease Brain and Its Implication in Mitochondrial Dysfunction

Genes ◽

10.3390/genes12060871 ◽

2021 ◽

Vol 12 (6) ◽

pp. 871

Author(s):

Eun-Gyung Lee ◽

Sunny Chen ◽

Lesley Leong ◽

Jessica Tulloch ◽

Chang-En Yu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Postmortem Brain ◽

Human Postmortem Brain ◽

Mitochondrial Dna Copy Number ◽

Mitochondrial Functions ◽

Differential Transcription ◽

And Control ◽

Rna Levels

Increasing evidence suggests that the Translocase of Outer Mitochondria Membrane 40 (TOMM40) gene may contribute to the risk of Alzheimer’s disease (AD). Currently, there is no consensus as to whether TOMM40 expression is up- or down-regulated in AD brains, hindering a clear interpretation of TOMM40’s role in this disease. The aim of this study was to determine if TOMM40 RNA levels differ between AD and control brains. We applied RT-qPCR to study TOMM40 transcription in human postmortem brain (PMB) and assessed associations of these RNA levels with genetic variants in APOE and TOMM40. We also compared TOMM40 RNA levels with mitochondrial functions in human cell lines. Initially, we found that the human genome carries multiple TOMM40 pseudogenes capable of producing highly homologous RNAs that can obscure precise TOMM40 RNA measurements. To circumvent this obstacle, we developed a novel RNA expression assay targeting the primary transcript of TOMM40. Using this assay, we showed that TOMM40 RNA was upregulated in AD PMB. Additionally, elevated TOMM40 RNA levels were associated with decreases in mitochondrial DNA copy number and mitochondrial membrane potential in oxidative stress-challenged cells. Overall, differential transcription of TOMM40 RNA in the brain is associated with AD and could be an indicator of mitochondrial dysfunction.

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Synapsin-Promoted Caveolin-1 Overexpression Maintains Mitochondrial Morphology and Function in PSAPP Alzheimer’s Disease Mice

Cells ◽

10.3390/cells10092487 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2487

Author(s):

Shanshan Wang ◽

Taiga Ichinomiya ◽

Yuki Terada ◽

Dongsheng Wang ◽

Hemal H. Patel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dynamics ◽

Neuronal Morphology ◽

Synaptic Function ◽

Scaffolding Protein ◽

Mitochondrial Morphology ◽

Caveolin 1 ◽

Synaptic Ultrastructure ◽

And Function

Mitochondrial dysfunction plays a pivotal role in the Alzheimer’s Disease (AD) pathology. Disrupted mitochondrial dynamics (i.e., fusion/fission balance), which are essential for normal mitochondria structure and function, are documented in AD. Caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein regulates metabolic pathways in several different cell types such as hepatocytes and cancer cells. Previously, we have shown decreased expression of Cav-1 in the hippocampus of 9-month (m) old PSAPP mice, while hippocampal overexpression of neuron-targeted Cav-1 using the synapsin promoter (i.e., SynCav1) preserved cognitive function, neuronal morphology, and synaptic ultrastructure in 9 and 12 m PSAPP mice. Considering the central role of energy production in maintaining normal neuronal and synaptic function and survival, the present study reveals that PSAPP mice exhibit disrupted mitochondrial distribution, morphometry, and respiration. In contrast, SynCav1 mitigates mitochondrial damage and loss and enhances mitochondrial respiration. Furthermore, by examining mitochondrial dynamics, we found that PSAPP mice showed a significant increase in the phosphorylation of mitochondrial dynamin-related GTPase protein (DRP1), resulting in excessive mitochondria fragmentation and dysfunction. In contrast, hippocampal delivery of SynCav1 significantly decreased p-DRP1 and augmented the level of the mitochondrial fusion protein, mitofusin1 (Mfn1) in PSAPP mice, a molecular event, which may mechanistically explain for the preserved balance of mitochondria fission/fusion and metabolic resilience in 12 m PSAPP-SynCav1 mice. Our data demonstrate the critical role for Cav-1 in maintaining normal mitochondrial morphology and function through affecting mitochondrial dynamics and explain a molecular and cellular mechanism underlying the previously reported neuroprotective and cognitive preservation induced by SynCav1 in PSAPP mouse model of AD.

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Lipid Rafts and Development of Alzheimer’s Disease

10.5772/intechopen.94608 ◽

2021 ◽

Author(s):

Mario Díaz ◽

Raquel Marin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipid Rafts ◽

Current Evidence ◽

Amyloid Beta Peptides ◽

Main Component ◽

And Function ◽

Human Brains ◽

Neuronal Physiology ◽

The Impact

A wealth of evidence accumulated over the last two decades has unambiguously linked lipid rafts to neurodegenerative diseases, in particular to Alzheimer’s disease (AD). These microdomains are highly dynamic membrane platforms with differentiated physicochemical and molecular properties compared to the surrounding membrane microenvironment, and are the locus for a number of central processes in neuronal physiology. Most recent evidence pinpoint to lipid rafts as main players in AD neuropathology. It is now widely accepted that lipid rafts actively participate in the processing of amyloid precursor protein to generate amyloid beta peptides, a main component of amyloid plaques. Current evidence have highlighted the existence of severe alterations in the molecular structure and functionality of lipid rafts in the frontal cortex of human brains affected by Alzheimer’s disease. An exceptionally interesting observation is that lipid raft destabilization can be demonstrated even at the earliest stages of AD neuropathology. In the present review, we will first elaborate on the structure and function of these multifaceted subcellular structures and second to focus on the impact of their alterations in neuronal pathophysiology along the onset and progression of AD continuum.

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Mitochondrial dysfunction in Alzheimer’s disease: Opportunities for drug development

Current Neuropharmacology ◽

10.2174/1570159x19666210517114016 ◽

2021 ◽

Vol 19 ◽

Author(s):

Shiveena Bhatia ◽

Rishi Rawal ◽

Pratibha Sharma ◽

Tanveer Singh ◽

Manjinder Singh ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Development ◽

Mitochondrial Dysfunction ◽

Cortical Neurons ◽

Brain Metabolism ◽

Senile Dementia ◽

Mitochondrial Morphology ◽

Drug Development Research ◽

The Brain

: Alzheimer’s disease (AD) is one of the major reasons for 60-80% of cases of senile dementia occurring as a result of the accumulation of plaques and tangles in the hippocampal and cortical neurons of the brain leading to neurodegeneration and cell death. The other pathological features of AD comprise of abnormal microvasculature, network abnormalities, interneuronal dysfunction, increased β-amyloid production, and reduced clearance, increased inflammatory response, elevated production of reactive oxygen species, impaired brain metabolism, hyperphosphorylation of tau, and disruption of acetylcholine signaling. Among all these pathologies, mitochondrial dysfunction (MD), regardless of being an inciting insult or a consequence of the alterations, is related to all the associated AD pathologies. Observed altered mitochondrial morphology, distribution, and movement increased oxidative stress, dysregulation of enzymes involved in mitochondrial functioning, impaired brain metabolism, and impaired mitochondrial biogenesis in AD subjects suggest the involvement of mitochondrial malfunction in the progression of AD. Various pre-clinical and clinical evidence establishing MD as a key mediator in the progression of neurodegeneration in AD are reviewed and discussed with an aim to foster future MD-based drug development research for the management of AD.

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