. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001 Jun 15;21(12):4183-7. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. Context of the study. A major question in the study of brain aging and dementia is: what insults initiate the cascade of pathology causing cognitive dysfunction and the emergence of brain pathology? The candidates are many but two central ones are β-amyloid accumulation and oxidative damage. In a recent study, Practico and coworkers analyze the relationship of increased lipid peroxidation and  β-amyloid accumulation in the brains of a transgenic mouse model (Tg2576). They focus on the isoprostane (8,12-iso-iPF2_-VI) that they have previously shown is elevated in urine, serum and CSF of Alzheimer's disease (AD) patients.  This is an important study for its mechanistic implications to the field as a whole as well as in bridging the gap between humans and animal models.

    Basic findings. Practico and coworkers find brain region differences in isoprostanes in the transgenics (cerebellum shows no increases, prefrontal and hippo show increases that precede amyloid) and the correlation between isoprostane levels and abeta  is 0.77 (the scatter graphs are convincing). Urine and plasma levels also rise in parallel and both these measures correlate with brain levels of  isoprostanes. Unfortunately they did not measure plasma β-amyloid. It would  have been important to see if plasma isoprostanes and β-amyloid were correlated or if one preceded the other. The one puzzling finding was the lack of age effect in the wildtype animals.  It would have been predicted there would be some age associated increases; however it is possible an 18 month old mouse is not that old (unlikely) or that this particular stain is very resistant to increases. The isoprostane levels in the wild types remained stable at all the ages sampled.

    Limitations and technical concerns. A few technical cautions in the interpretation are warranted. The authors only looked at total β-amyloid (ie. extracted all brain samples with formic acid) and there is a good chance that soluble β-amyloid (SDS fraction) may have produced different results. Indeed, in AD soluble β-amyloid precedes the mass build up of insoluble β-amyloid. Thus this remains an open question. It is also important to note that the transgenic model does show significantly different features from even incipient AD such as the major form of β-amyloid in the mouse is Aβ 1-40 whereas in the human Aβ1-42prevails (see Kawarabayashi, etal, for example). Nonetheless this paper establishes that in the mouse lipid peroxidation is an early event and that it precedes the massive build up of insoluble β-amyloid. Of course, other markers need to be examined including protein and nucleic acid oxidative damage.

    The next steps

    The authors conclude that oxidative damage contributes to AD pathogenesis before β-amyloid accumulation in the AD brain. Maybe?! Overall, the results are not inconsistent with more limited studies on the AD brain by a variety of investigators. A critical test of the hypothesis is now feasible: does an antioxidant intervention delay or arrest the build up of β-amyloid?

    What does this imply for β-amyloid as a primary risk factor in disease cascades?  Because of the protracted and progressive nature of AD, Aβ may be present in the brain at sublethal concentrations for extended periods.  Although at these levels Aβ may not compromise neuron survival, it may affect critical signal transduction processes and induce gene expression patterns that render cells at progressively greater risk for death. Thus, in addition to its own inherent bioactivity, Aβ is likely to contribute to diverse molecular cascades and amplify the adverse consequences of other insults, such as oxidative stress, oxygen/glucose deprivation, excitotoxicity, etc.  Hence, Aβ may be a critical driving factor in a variety of pathological mechanisms in AD; the relative contribution of these mechanisms to neuronal loss and cognitive decline may change over time, dependent upon the influence of age, relative levels and types of Aβ present, and the presence/absence of additional insults.  We have suggested such a prolonged checkpoint process for cell dysfunction/death may be at work in AD.  Indeed, antioxidants may be one of the factors that should slow the insidious cascade of events. Animal experiments such as reported this important paper help to support the need for a primary prevention trail to prevent dementia.
    —Carl W. Cotman, Director, Institute for Brain Aging and Dementia, Professor of Psychobiology, Professor of Neurology, University of California, Irvine

    See also:

    Cotman, C.W., K.J. Ivins, and A.J. Anderson, Apoptosis in Alzheimer Disease, in Alzheimer Disease, R.K. R. DD Terry, K. L. Buck, and S. S. Sisodia, Editor. 1999, Lippencott Williams & Wilkins: Philadelphia.

    ScienceDaily Story: Penn Study Findings Reverse Key Chronology For Development Of Alzheimer's Disease

     

    References:

    . Apoptosis decision cascades and neuronal degeneration in Alzheimer's disease. Neurobiol Aging. 1998 Jan-Feb;19(1 Suppl):S29-32. PubMed.

    . Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci. 2001 Jan 15;21(2):372-81. PubMed.

  2. Oxidative Abnormalities As The Earliest Changes In Amyloid-b Disease

    Determining the chronological and mechanistic interrelationship of Alzheimer disease (AD) is critical to both elucidating its etiology and developing efficacious therapeutics that are directed at the most fundamental changes. Currently, approved therapeutics are directed to neurotransmitter deficits and most work targeted at developing new therapeutics is centered on reversing the pathological changes.

    However, there is reason to think that this strategy is fundamentally flawed (Perry et al., 2000). Indeed, researchers from the University of Pennsylvania have now extended prior work on oxidative damage in transgenic mice (Pappolla et al., 1998; Smith et al., 1998) overexpressing amyloid b-protein precursor (AbPP) by showing that oxidative stress chronologically precedes increased amyloid-b(Ab).

    These exciting findings are in line with studies of cells showing oxidative stress induced AbPP synthesis and Ab formation (Yan et al., 1994) as well as the temporal supremacy of oxidative damage over Ab in Down syndrome (Nunomura et al., 1999) and AD (Nunomura et al., 2001).

    That in all these systems (cellular, transgenic mice and human disease) oxidative damage shows temporal supremacy is strong evidence against Ab being the major source of reactive oxygen in AD. In fact, these studies point to Ab as a consequence of oxidative stress rather than a cause. Therefore, it is likely that a fuller mechanistic/therapeutic understanding of AD will come from understanding the basis for increased oxidative damage rather than studying its consequences.—George Perry and Mark Smith, Institute of Pathology, Case Western Reserve University, Cleveland, Ohio

    References:

    . Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.

    . RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease. J Neurosci. 1999 Mar 15;19(6):1959-64. PubMed.

    . Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol. 1998 Apr;152(4):871-7. PubMed.

    . Amyloid-beta junkies. Lancet. 2000 Feb 26;355(9205):757. PubMed.

    . Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998 May;70(5):2212-5. PubMed.

    . Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7787-91. PubMed.

This paper appears in the following:

Webinars

  1. Making a BioMark on Alzheimer Disease