Defective mitophagy and synaptic degeneration in Alzheimer's disease: Focus on aging, mitochondria and synapse

Morton, Hallie; Kshirsagar, Sudhir; Orlov, Erika; Bunquin, Lloyd E; Sawant, Neha; Boleng, Lauren; George, Mathew; Basu, Tanisha; Ramasubramanian, Bhagavathi; Pradeepkiran, Jangampalli Adi; Kumar, Subodh; Vijayan, Murali; Reddy, Arubala P.; Reddy, P. Hemachandra

doi:10.1016/j.freeradbiomed.2021.07.013

Cited by 101 publications

(57 citation statements)

References 137 publications

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“…Dysregulation of mitophagy has been accompanied with TBI pathophysiology (95,96). Mitophagy is also well implicated in Alzheimer's disease, Parkinson's disease, cerebral ischemia, multiple sclerosis, diabetes, and obesity with involvements of Dynamin-1-like protein (Drp1) (97)(98)(99). In our studies using proteome analysis of brain tissue, we reported that overpressure of 46.7 kPa caused dysregulation of fission-fusion processes underlying mitophagy, evidenced by decreased Drp1, and changes in fission protein (Fis1), inner membrane fusion protein (OPA1) and outer membrane fusion protein (mitofusin 2) at 7-and 30-days post-blast (50).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

et al. 2022

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Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

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Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

et al. 2022

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“…Deletion of mitochondrial ubiquitin ligase, which is involved in mitochondrial dynamics and functions and is dysregulated in AD, initiates mitochondrial impairments and worsens cognitive decline in a mouse model with AD-related Aβ pathology [ 48 ]. Other studies have examined the triggering of apoptotic cascades and organelle swelling following exposure of mitochondria to Aβ [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”

Section: Mitochondrial Impairment In Admentioning

confidence: 99%

Disentangling Mitochondria in Alzheimer’s Disease

Johri

2021

IJMS

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Alzheimer’s disease (AD) is a major cause of dementia in older adults and is fast becoming a major societal and economic burden due to an increase in life expectancy. Age seems to be the major factor driving AD, and currently, only symptomatic treatments are available. AD has a complex etiology, although mitochondrial dysfunction, oxidative stress, inflammation, and metabolic abnormalities have been widely and deeply investigated as plausible mechanisms for its neuropathology. Aβ plaques and hyperphosphorylated tau aggregates, along with cognitive deficits and behavioral problems, are the hallmarks of the disease. Restoration of mitochondrial bioenergetics, prevention of oxidative stress, and diet and exercise seem to be effective in reducing Aβ and in ameliorating learning and memory problems. Many mitochondria-targeted antioxidants have been tested in AD and are currently in development. However, larger streamlined clinical studies are needed to provide hard evidence of benefits in AD. This review discusses the causative factors, as well as potential therapeutics employed in the treatment of AD.

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“…Dysfunctional mitochondria are an early feature of neurodegenerative diseases [ 21 ] and early responses to excessive production of reactive oxygen species (ROS) result in the induction of mitophagy to remove damaged mitochondria. Mitochondrial damage associated with sustained oxidative stress, as in the exposure to air pollutants and NPs, overwhelms autophagic and mitophagic pathways, activating a vicious circle that leads to reduced capacity to remove damaged mitochondria, and/or an alteration in the regulation of mitophagy [ 21 ]. Defective mitophagy leads to synaptic degeneration and mitochondrial fragmentation in association with Aβ and P-tau and cognitive dysfunction in Alzheimer’s disease (AD) [ 21 ].…”

Section: Portals Of Entry To the Brain And Key Neural Damage Mechanismsmentioning

confidence: 99%

“…Mitochondrial damage associated with sustained oxidative stress, as in the exposure to air pollutants and NPs, overwhelms autophagic and mitophagic pathways, activating a vicious circle that leads to reduced capacity to remove damaged mitochondria, and/or an alteration in the regulation of mitophagy [ 21 ]. Defective mitophagy leads to synaptic degeneration and mitochondrial fragmentation in association with Aβ and P-tau and cognitive dysfunction in Alzheimer’s disease (AD) [ 21 ]. NPs are very effective in targeting the cell powerhouse in neural cells in air pollution-exposed children and young adults ( Figure 2 ).…”

Section: Portals Of Entry To the Brain And Key Neural Damage Mechanismsmentioning

confidence: 99%

Particulate Air Pollution and Risk of Neuropsychiatric Outcomes. What We Breathe, Swallow, and Put on Our Skin Matters

Calderón‐Garcidueñas

Stommel

Rajkumar

et al. 2021

IJERPH

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We appraise newly accumulated evidence of the impact of particle pollution on the brain, the portals of entry, the neural damage mechanisms, and ultimately the neurological and psychiatric outcomes statistically associated with exposures. PM pollution comes from natural and anthropogenic sources such as fossil fuel combustion, engineered nanoparticles (NP ≤ 100 nm), wildfires, and wood burning. We are all constantly exposed during normal daily activities to some level of particle pollution of various sizes—PM2.5 (≤2.5 µm), ultrafine PM (UFP ≤ 100 nm), or NPs. Inhalation, ingestion, and dermal absorption are key portals of entry. Selected literature provides context for the US Environmental Protection Agency (US EPA) ambient air quality standards, the conclusions of an Independent Particulate Matter Review Panel, the importance of internal combustion emissions, and evidence suggesting UFPs/NPs cross biological barriers and reach the brain. NPs produce oxidative stress and neuroinflammation, neurovascular unit, mitochondrial, endoplasmic reticulum and DNA damage, protein aggregation and misfolding, and other effects. Exposure to ambient PM2.5 concentrations at or below current US standards can increase the risk for TIAs, ischemic and hemorrhagic stroke, cognitive deficits, dementia, and Alzheimer’s and Parkinson’s diseases. Residing in a highly polluted megacity is associated with Alzheimer neuropathology hallmarks in 99.5% of residents between 11 months and ≤40 y. PD risk and aggravation are linked to air pollution and exposure to diesel exhaust increases ALS risk. Overall, the literature supports that particle pollution contributes to targeted neurological and psychiatric outcomes and highlights the complexity of the pathophysiologic mechanisms and the marked differences in pollution profiles inducing neural damage. Factors such as emission source intensity, genetics, nutrition, comorbidities, and others also play a role. PM2.5 is a threat for neurological and psychiatric diseases. Thus, future research should address specifically the potential role of UFPs/NPs in inducing neural damage.

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Defective mitophagy and synaptic degeneration in Alzheimer's disease: Focus on aging, mitochondria and synapse

Cited by 101 publications

References 137 publications

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Disentangling Mitochondria in Alzheimer’s Disease

Particulate Air Pollution and Risk of Neuropsychiatric Outcomes. What We Breathe, Swallow, and Put on Our Skin Matters

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