Evidence for Apoptotic Cell Death in Alzheimer's Disease

Smale, Georgeann; Nichols, Nancy R.; Brady, Daniel R.; Finch, Caleb E.; Horton, Walter E.

doi:10.1006/exnr.1995.1025

Cited by 454 publications

(228 citation statements)

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“…Our findings are consistent with previous observations of increased ceramide, TUNEL staining and caspase activation in postmortem AD brain (Gervais et al, 1999;Smale et al, 1995), and decreased sphingomyelin (Gottfries et al, 1996;Soderberg et al, 1992). In addition, we have demonstrated a new possible mechanism by which accumulation of Aβ, which is believed to be one of the key pathologic mechanisms leading to AD, contributes to neuronal death via activation of the sphingomyelin/ceramide pathway.…”

Section: Discussionsupporting

confidence: 92%

Deregulation of sphingolipid metabolism in Alzheimer's disease

Huang²,

Li³

et al. 2010

Neurobiology of Aging

442

468

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Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta peptide (Aβ) and phosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Aβ oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pretreatment of the neurons with purified, recombinant AC prevented the cells from undergoing Aβ-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Aβ deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis.

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Section: Discussionsupporting

confidence: 92%

Deregulation of sphingolipid metabolism in Alzheimer's disease

Huang²,

Li³

et al. 2010

Neurobiology of Aging

442

468

View full text Add to dashboard Cite

show abstract

“…Astrocytes make rapid responses to numerous varieties of damage and pathological changes through a process referred to as reactive astrogliosis. Evidence of astrogliosis has been documented in early stages of AD (Schipper et al 2006;Owen et al 2009;Carter et al 2012), whereas astrocyte death or atrophy in AD brains from patients and animal models has also been reported (Smale et al 1995;Kobayashi et al 2002Kobayashi et al , 2004. Extensive gliosis is present in the hippocampus of adult APP/PS1 mice .…”

Section: Discussionmentioning

confidence: 99%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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“…Likewise, oxidative stress conditions can also initiate early apoptosis, known to play an important role in neuronal loss in vitro and in vivo in AD (Cotman and Anderson, 1995;Cras et al, 1995;Honig and Rosenberg, 2000;MacGibbon et al, 1997;Smale et al, 1995); however, not much is known about apoptotic pathways in MCI. Several studies have found increased Bcl-2 expression in the hippocampus and entorhinal cortex of AD brains (Satou et al, 1995;Su et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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Evidence for Apoptotic Cell Death in Alzheimer's Disease

Cited by 454 publications

References 0 publications

Deregulation of sphingolipid metabolism in Alzheimer's disease

Deregulation of sphingolipid metabolism in Alzheimer's disease

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

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