Mitochondrial Targeting of Amyloid-β Protein Precursor Intracellular Domain Induces Hippocampal Cell Death via a Mechanism Distinct from Amyloid-β

Sandberg, Alexandra A.; Manning, Evan; Wilkins, Heather; Mazzarino, Randall C.; Minckley, Taylor; Swerdlow, Russell H.; Patterson, David; Qin, Yan; Linseman, Daniel A.

doi:10.3233/jad-215108

Cited by 5 publications

(4 citation statements)

References 56 publications

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“…CHCHD6 regulates mitochondrial contact site and cristae organization [ 65 ]. When AICD is specifically targeted to mitochondria it induces apoptosis in a hippocampal cell line, and this effect could be rescued with antioxidants and caspase inhibitors [ 66 ]. The effects of AICD on mitochondria are likely due to its ability to change gene transcription in the nucleus and its localization within mitochondria.…”

Section: The Effects Of App and App Processing On Mitochondriamentioning

confidence: 99%

Interactions between amyloid, amyloid precursor protein, and mitochondria

Wilkins

2023

Biochemical Society Transactions

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Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), of which Aβ is generated from, is found within mitochondria. Studies suggest Aβ can be generated in mitochondria and imported into mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. The role these interactions contribute to AD pathology and progression are unknown. Here, we discuss prior research, the rigor of those studies, and the critical knowledge gaps of relationships between APP, Aβ, and mitochondria.

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Section: The Effects Of App and App Processing On Mitochondriamentioning

confidence: 99%

Interactions between amyloid, amyloid precursor protein, and mitochondria

Wilkins

2023

Biochemical Society Transactions

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“…Mitochondria with low bioenergetic potential have increased APP translocation and express more Aβ, suggesting that APP targets these impaired mitochondria and that decreased fluid Aβ42/Aβ40 ratio may actually be a biomarker for impaired mitochondrial bioenergetics ( Wilkins et al, 2022 ). Increased Aβ production within the mitochondria also results in higher inner mitochondrial AICD, which is neurotoxic in a manner independent of Aβ ( Sandberg et al, 2022 ). In vivo studies in mouse models suggest that APP processing can be altered via bioenergetic manipulation.…”

Section: Amyloid-β and Alzheimer’s Diseasementioning

confidence: 99%

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is a progressive neurodegenerative condition characterized by clinical decline in memory and other cognitive functions. A classic AD neuropathological hallmark includes the accumulation of amyloid-β (Aβ) plaques, which may precede onset of clinical symptoms by over a decade. Efforts to prevent or treat AD frequently emphasize decreasing Aβ through various mechanisms, but such approaches have yet to establish compelling interventions. It is still not understood exactly why Aβ accumulates in AD, but it is hypothesized that Aβ and other downstream pathological events are a result of impaired bioenergetics, which can also manifest prior to cognitive decline. Evidence suggests that individuals with AD and at high risk for AD have functional brain ketone metabolism and ketotherapies (KTs), dietary approaches that produce ketone bodies for energy metabolism, may affect AD pathology by targeting impaired brain bioenergetics. Cognitively normal individuals with elevated brain Aβ, deemed “preclinical AD,” and older adults with peripheral metabolic impairments are ideal candidates to test whether KTs modulate AD biology as they have impaired mitochondrial function, perturbed brain glucose metabolism, and elevated risk for rapid Aβ accumulation and symptomatic AD. Here, we discuss the link between brain bioenergetics and Aβ, as well as the potential for KTs to influence AD risk and progression.

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“…Some have claimed that both Aβ accumulation and mitochondrial failure are critical to the development of AD and may act synergistically [218,219]. The problem with this theory is that most of the Aβ deposition is extracellular, although some argue for the role of intraneuronal Aβ [220].…”

Section: Limitations Of the Hypothesis That Ad Is Driven By Mitochond...mentioning

confidence: 99%

Mitochondria in Alzheimer’s Disease Pathogenesis

Reiss,

Gulkarov,

Jacob

et al. 2024

Life

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Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.

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Mitochondrial Targeting of Amyloid-β Protein Precursor Intracellular Domain Induces Hippocampal Cell Death via a Mechanism Distinct from Amyloid-β

Cited by 5 publications

References 56 publications

Interactions between amyloid, amyloid precursor protein, and mitochondria

Interactions between amyloid, amyloid precursor protein, and mitochondria

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

Mitochondria in Alzheimer’s Disease Pathogenesis

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