Deficiency in Mitochondrial Aldehyde Dehydrogenase Increases the Risk for Late-Onset Alzheimer's Disease in the Japanese Population

Kamino, Kouzin; Nagasaka, Keiko; Imagawa, Masaki; Yamamoto, Hideki; Yanagawa, Hiroshi; Ueki, Akira; Kitamura, Shin; Namekata, Kazuhiko; Miki, Tetsuro; Ohta, Shigeo

doi:10.1006/bbrc.2000.2923

Cited by 156 publications

(138 citation statements)

References 33 publications

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“…Thus, APOE eliminates free HNE and the possession of APOE-4, the APOE with the weakest HNE elimination ability, leading to the accumulation of HNE in neurons and increasing oxidative stress. These results agree with our previous epidemiological investigation (Kamino et al, 2000), in which ALDH2*2 and APOE-4 alleles synergistically increased the risk of AD. Together, the accumulation of HNE in ALDH2-deficient mice is further intensified by the loss of ApoE.…”

Section: Discussionsupporting

confidence: 93%

“…We reported previously that a molecular epidemiological analysis revealed a higher concentration of lipid peroxides (LPOs) in the sera of ALDH2-deficient females than in those carrying an active ALDH2 (Ohsawa et al, 2003b), and that ALDH2 deficiency is a risk factor for late-onset AD, synergistically acting with the 4 allele of the apolipoprotein E gene (APOE-4 ) (Kamino et al, 2000). This finding was recently confirmed by studies in China and Korea (Jo et al, 2007;Wang et al, 2008).…”

Section: Introductionmentioning

confidence: 81%

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Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

Ohsawa

Nishimaki²,

Murakami³

et al. 2008

Journal of Neuroscience

102

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Oxidative stress may underlie age-dependent memory loss and cognitive decline. Toxic aldehydes, including 4-hydroxy-2-nonenal (HNE), an end product of lipid peroxides, are known to accumulate in the brain in neurodegenerative disease. We have previously shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies HNE by oxidizing its aldehyde group. To investigate the role of such toxic aldehydes, we produced transgenic mice, which expressed a dominant-negative form of ALDH2 in the brain. The mice had decreased ability to detoxify HNE in their cortical neurons and accelerated accumulation of HNE in the brain. Consequently, their lifespan was shortened and age-dependent neurodegeneration and hyperphosphorylation of tau were observed. Object recognition and Morris water maze tests revealed that the onset of cognitive impairment correlated with the degeneration, which was further accelerated by APOE (apolipoprotein E) knock-out; therefore, the accumulation of toxic aldehydes is by itself critical in the progression of neurodegenerative disease, which could be suppressed by ALDH2.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 81%

Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

Ohsawa

Nishimaki²,

Murakami³

et al. 2008

Journal of Neuroscience

102

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“…Mitochondrial dysfunction in AD (21,(65)(66)(67) varies with apoE genotype, being greater in apoE4 than in apoE3 carriers (19). ApoE4 is also associated with decreased cerebral glucose metabolism in both AD patients and nondemented subjects (68)(69)(70)(71).…”

Section: Discussionmentioning

confidence: 99%

Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity

Chang

Tian

Miranda

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

277

275

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Apolipoprotein (apo) E4, a 299-aa protein and a major risk factor for Alzheimer's disease, can be cleaved to generate C-terminaltruncated fragments that cause neurotoxicity in vitro and neurodegeneration and behavioral deficits in transgenic mice. To investigate this neurotoxicity, we expressed apoE4 with C-or N-terminal truncations or mutations in transfected Neuro-2a cells. ApoE4 Alzheimer's disease ͉ mitochondria ͉ proteolysis H uman apolipoprotein (apo) E, a 34-kDa protein with 299 aa, has three major isoforms, apoE2, apoE3, and apoE4 (1-4). ApoE4 is a major risk factor for Alzheimer's disease (AD) (5-7). The apoE4 allele, which is found in 40-65% of cases of sporadic and familial AD, increases the occurrence and lowers the age of onset of the disease (7,8).Biochemical, cell biological, transgenic animal, and human studies have suggested several potential mechanisms to explain the contribution of apoE4 to the pathogenesis of AD. These mechanisms include modulation of the deposition and clearance of amyloid ␤ (A␤) peptides and the formation of plaques (9 -15), modulation of A␤-caused synaptic and cholinergic deficits (16), acceleration of age-and excitotoxicity-related neurodegeneration (17), impairment of the antioxidative defense system and mitochondrial function (18 -21), dysregulation of neuronal signaling pathways (22), altered phosphorylation of tau and neurofibrillary tangle formation (23-28), depletion of cytosolic androgen receptor levels in the brain (29, 30), potentiation of A␤-induced lysosomal leakage and apoptosis in neuronal cells (31), and promotion of endosomal abnormalities linked to A␤ overproduction (32-34). The mechanisms of these apoE4-mediated detrimental effects are largely unknown.We have shown that apoE can be cleaved by a neuronspecific chymotrypsin-like serine protease that generates bioactive C-terminal-truncated forms of apoE (25,27,28). The fragments are found at higher levels in the brains of AD patients than in age-and sex-matched controls (27), and apoE4 is more susceptible to cleavage than apoE3. When expressed in cultured neuronal cells or added exogenously to the cultures, apoE4 fragments are neurotoxic, leading to cell death (25). When expressed in transgenic mice, they cause AD-like neurodegeneration and behavioral deficits (27). Because apoE is synthesized by neurons under diverse pathophysiological conditions (35-49), we hypothesize that apoE4 produced in neurons in response to stress or injury (e.g., A␤ toxicity, brain trauma, or oxidative stress) is uniquely susceptible to proteolytic cleavage and that the resulting bioactive C-terminaltruncated fragments induce neuropathology and associated behavioral deficits. ApoE3 also undergoes proteolytic cleavage but to a lesser extent.In this study, we investigated the cellular and molecular mechanisms of the neurotoxicity caused by apoE4 fragments in cultured neuronal cells. We also evaluated the roles of various regions [specifically, the receptor-binding region (amino acids 135-150) and the lipid-binding region (amino acid...

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“…With aging, dysfunction of these enzymes may cause abnormalities in the formaldehyde cycle and aberrant enzymatic production of FA from endogenous and exogenous substrates results in the accumulation of FA, leading to stress and subsequent pathogenic neurodegeneration (Morrison et al, 1996;Tyihak et al, 1998;Kamino et al, 2000;Yu et al, 2003b;Unzeta et al, 2005;Unzeta et al, 2007). Other factors in aging can also produce excess endogenous FA.…”

Section: Putative Mechanism Of Formaldehyde Accumulation and Formaldementioning

confidence: 99%

Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

Miao¹,

He²

2012

Neurodegeneration

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Deficiency in Mitochondrial Aldehyde Dehydrogenase Increases the Risk for Late-Onset Alzheimer's Disease in the Japanese Population

Cited by 156 publications

References 33 publications

Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

Age-Dependent Neurodegeneration Accompanying Memory Loss in Transgenic Mice Defective in Mitochondrial Aldehyde Dehydrogenase 2 Activity

Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity

Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

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