Mitochondrial Abnormalities in Alzheimer's Disease

Hirai, Keisuke; Aliev, Gjumrakch; Nunomura, Akihiko; Fujioka, Hisashi; Russell, Robert L.; Atwood, Craig S.; Johnson, Anne B.; Kress, Yvonne; Vinters, Harry V.; Tabaton, Massimo; Shimohama, Shun; Cash, Adam D.; Siedlak, Sandra L.; Harris, Peggy L.R.; Jones, Paul K.; Petersen, Robert B.; Perry, George; Smith, Mark A.

doi:10.1523/jneurosci.21-09-03017.2001

Cited by 1,243 publications

(1,051 citation statements)

References 34 publications

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“…Mitochondrial dysfunction is an early and causal step in AD pathology, tightly linked to neurodegeneration and promoting cognitive impairment (Hirai et al., 2001; Swerdlow, Burns & Khan, 2014; Swerdlow & Khan, 2009; Swerdlow et al., 2010). The apoptotic outcome has been attributed to the pathological effects of Aβ intermediate aggregation species (particularly oligomers and protofibrils) on mitochondrial pathways (Fossati et al., 2010, 2012b).…”

Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

et al. 2018

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SummaryMounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid β (Aβ)‐mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Aβ, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H2O2 generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Aβ‐induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA‐approved drugs with a well‐known profile of brain delivery.

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Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

et al. 2018

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“…Although mitochondria possess various iron containing functional molecules, such as heme, cytochrome, and aconitase, little 8OHG is accumulated. On the other hand in situ hybridization and ultrastructural observations reveal that mitochondrial abnormalities exist in AD brain and many abnormal mitochondria are targeted to lysosomes [60]. Since lysosomes also accumulate iron, mitochondrial turnover and lysosomal activity are a potential metabolic source of iron within damaged cells.…”

Section: Iron In Neurofibrillary Tanglesmentioning

confidence: 99%

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

et al. 2007

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Although iron is essential in maintaining the function of the central nervous system, it is a potent source of reactive oxygen species. Excessive iron accumulation occurs in many neurodegenerative diseases including Alzheimer disease (AD), Parkinson's disease, and Creutzfeldt-Jakob disease, raising the possibility that oxidative stress is intimately involved in the neurodegenerative process. AD in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

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“…How this in turn leads to their apoptosis remains unclear, but one proposed mechanism is ''mitochondrial stasis'', whereby the mitochondria that duplicate during late G 2 and S phases fail to redistribute through cytokinesis. (20,21) This mitochondrial surplus in metabolically active neurons is thought to create reduction-oxidation (redox) imbalances that overwhelm endogenous antioxidant activities. Alternatively, one can imagine that the increased concentration of mitochondria sensitizes cell to apoptotic signals, such as Bax, that are normally transduced through these organelles.…”

Section: Introductionmentioning

confidence: 99%

Tumorigenesis and neurodegeneration: two sides of the same coin?

Staropoli

2008

BioEssays

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SummaryDysregulation of genes that control cell-cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post-mitotic neurons under certain conditions. The gene for ataxiatelangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss-of-function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss-of-function mutations in which account for about half of cases of early-onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re-expression sensitizes derivative cell lines to inhibitors of cell-cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long-held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders.

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Mitochondrial Abnormalities in Alzheimer's Disease

Cited by 1,243 publications

References 34 publications

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

Tumorigenesis and neurodegeneration: two sides of the same coin?

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