Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-17T00:17:42.544Z Has data issue: false hasContentIssue false
  • English
  • Français

Brain aging and late-onset Alzheimer's disease: many open questions

Published online by Cambridge University Press:  12 July 2012

Christian Behl
Christian Behl*
Affiliation:
Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University Mainz, Germany
*
Correspondence should be addressed to: Christian Behl, Director, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University Mainz, D-55099 Mainz, Germany. Phone: +49 6131 3925890; Fax: +49 6131 39 25792. Email: [email protected].
Get access Rights & Permissions [Opens in a new window]

Abstract

Despite decades of research in the field of Alzheimer's disease (AD), a real understanding of its molecular pathophysiology and treatments relevant to the day-to-day lives of patients remain out of reach. Research has, with good reason, focused on certain key pathways and potential mechanisms, but sometimes this has been at the expense of work on other theories, which may be slowing down progress in this field. Interesting theories at present include oxidative stress and caloric restriction. Work on the Aβ cascade should continue but with a shift in focus to its intracellular effects and an awareness that additional pathogenetic factors and processes must be involved – most importantly, brain aging. Hyperphosphorylation of tau, for instance, provides another interesting pathway, with one old drug showing promise in this regard. Moreover, work in epigenetics and on protein homeostasis has produced interesting findings and both lines of investigation may reveal suitable targets for future intervention. Taken together, analysis of the biochemistry of aged neurons and the interplay with pathways of neurodegeneration may lead to a better understanding of AD and how to treat and prevent this condition.

Keywords

agingamyloidcaloric restrictiondementiaepigeneticsmetforminmethylene blueoxidative stressprotein homeostasistau hyperphosphorylation
Type
Research Article
Information
International Psychogeriatrics , Volume 24 , Supplement S1: The aging brain: current concepts, intervention strategies and the role of Ginkgo biloba extract EGb 761 , August 2012 , pp. S3 - S9
Copyright
Copyright © International Psychogeriatric Association 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Allsopp, R. C. and Harley, C. B. (1995). Evidence for a critical telomere length in senescent human fibroblasts. Experimental Cell Research, 219, 130–136.CrossRefGoogle ScholarPubMed
Behl, C. (2002). Oestrogen as a neuroprotective hormone. Nature Reviews Neuroscience, 3, 433–442.CrossRefGoogle ScholarPubMed
Behl, C. (2011). BAG3 and friends: co-chaperones in selective autophagy during aging and disease. Autophagy, 7, 795–798.CrossRefGoogle ScholarPubMed
Behl, C., Davis, J. B., Lesley, R. and Schubert, D. (1994). Hydrogen peroxide mediates amyloid beta protein toxicity. Cell, 77, 817–827.CrossRefGoogle ScholarPubMed
Caijgas, I. J., Will, T. and Schuman, E. M. (2010). Protein homeostasis and synaptic plasticity. EMBO Journal, 29, 2746–2752.CrossRefGoogle Scholar
Cheney, K. E. and Walford, R. L. (1974). Immune function and dysfunction in relation to aging. Life Sciences, 14, 2075–2084.CrossRefGoogle ScholarPubMed
Citron, M. (2010). Alzheimer's disease: strategies for disease modification. National Review of Drug Discoveries, 9, 387–398.CrossRefGoogle ScholarPubMed
Clement, A. B., Gimpl, G. and Behl, C. (2010). Oxidative stress resistance in hippocampal cells is associated with altered membrane fluidity and enhanced nonamyloidogenic cleavage of endogenous amyloid precursor protein. Free Radical Biology and Medicine, 48, 1236–1241.CrossRefGoogle ScholarPubMed
Colman, R. J. et al. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science, 325 (5937), 201–204CrossRefGoogle ScholarPubMed
Eckert, A., Schmitt, K. and Götz, J. (2011). Mitochondrial dysfunction: the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity. Alzheimer's Research and Therapy, 3, 15.CrossRefGoogle ScholarPubMed
Garmerdinger, M., Kaya, A. M., Wofrum, U., Clement, A. M. and Behl, C. (2011). BAG3 mediates chaperon-based aggresome-targeting and selective autophagy of misfolded proteins. EMBO Report, 12, 149–156.CrossRefGoogle Scholar
Greeve, I. et al. (2000). The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress. Journal of Neuroscience, 20, 7345–7352.CrossRefGoogle ScholarPubMed
Harman, D. (1965). The free radical theory of aging: effect of age on serum copper levels. Journal of Gerontology, 20, 151–153.CrossRefGoogle ScholarPubMed
Hayflick, L. and Moorhead, P. S. (1961). The serial cultivation of human diploid cell strains. Experimental Cell Research, 25, 585–621.CrossRefGoogle ScholarPubMed
Holmes, C. et al. (2008). Long-term effects of Aβ 42 immunisation in Alzheimer's disease: follow-up of a randomized placebo-controlled phase I trial. Lancet, 372 (9634), 216–223.CrossRefGoogle ScholarPubMed
Kickstein, E. et al. (2010). Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proceedings of the National Academy of Sciences of the United States of America, 107, 21830–21835.CrossRefGoogle ScholarPubMed
Lezoualc'h, F., Sagara, Y., Holsboer, F. and Behl, C. (1998). High constitutive NF-κB activity mediates resistance to oxidative stress in neuronal cells. Journal of Neuroscience, 18, 3224–3232.CrossRefGoogle ScholarPubMed
McGuffee, S. R. and Elcock, A. H. (2010). Diffusion, crowding and protein stability in a dynamic molecular model of the bacterial cytoplasm. PLoS Computational Biology, 6, e1000694.CrossRefGoogle Scholar
Mocko, J. B., Kern, A., Moosmann, B., Behl, C. and Hajieva, P. (2010). Phenothiazines interfere with dopaminergic neurodegeneration in Caenorhabditis elegans models of Parkinson's disease. Neurobiology of Disease, 40, 120–129.CrossRefGoogle ScholarPubMed
Moosmann, B. and Behl, C. (1999). The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proceedings of the National Academy of Sciences of the United States of America, 96, 8867–8872.CrossRefGoogle ScholarPubMed
Müller, W. E., Eckert, A., Kurz, C., Eckert, G. P. and Leuner, K. (2010). Mitochondrial dysfunction: common final pathway in brain aging and Alzheimer's disease – therapeutic aspects. Molecular Neurobiology, 41, 159–171.CrossRefGoogle ScholarPubMed
Narayan, P. J. and Dragunow, M. (2010). High content analysis of histone acetylation in human cells and tissues. Journal of Neuroscience Methods, 193, 54–61.CrossRefGoogle ScholarPubMed
Noble, W., Pooler, A. M. and Hanger, D. P. (2011). Advances in tau-based drug discovery. Expert Opinion in Drug Discoveries, 6, 797–810.CrossRefGoogle ScholarPubMed
Pimplikar, S. W., Nixon, R. A., Robakis, N. K., Shen, J. and Tsai, L. H. (2010). Amyloid-independent mechanisms in Alzheimer's disease pathogenesis. Journal of Neuroscience, 30, 14946–14954.CrossRefGoogle ScholarPubMed
Sagara, Y., Dargusch, R., Klier, F. G., Schubert, D. and Behl, C. (1996). Increased antioxidant enzyme activity in amyloid beta protein-resistant cells. Journal of Neuroscience, 16, 497–505.CrossRefGoogle ScholarPubMed
Schirmer, R. H., Adler, H., Pickhardt, M. and Mandelkow, E. (2011). “Less we forget you-methylene blue.” Neurobiology of Aging, 32, 2325 e7–16CrossRefGoogle Scholar
Seshadri, S. et al. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. New England Journal of Medicine, 346, 476–483.CrossRefGoogle ScholarPubMed
Shen, W. and Ganetzky, , , B. (2009). Autophagy promotes synapse development in Drosophila. Journal of Cell Biology, 187, 71–79.CrossRefGoogle ScholarPubMed
Soto, C. (2003). Unfolding the role of protein misfolding in neurodegenerative diseases. Nature Reviews Neuroscience, 4, 49–60.CrossRefGoogle ScholarPubMed
Stadtman, E. R. (2006). Protein oxidation and aging. Free Radical Research, 40, 1250–1258.CrossRefGoogle ScholarPubMed
Thinakaran, G. and Koo, E. H. (2008). Amyloid precursor protein trafficking, processing, and function. Journal of Biological Chemistry, 283, 29615–29619.CrossRefGoogle ScholarPubMed
Tohgi, H., Utsugisawa, K., Nagane, Y., Yoshimura, M., Genda, Y. and Ukitsu, M. (1999). Reduction with age in methylcytosine in the promoter region -224 approximately -101 of the amyloid precursor protein gene in autopsy human cortex. Brain Research Molecular Brain Research, 70, 288–292.CrossRefGoogle ScholarPubMed
West, R. L., Lee, J. M. and Maroun, L. E. (1995). Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient. Journal of Molecular Neuroscience, 6, 141–146.CrossRefGoogle ScholarPubMed
Willeumier, K., Pulst, S. M. and Schweizer, F. E. (2006). Proteasome inhibition triggers activity-dependent increase in the size of the recycling vesicle pool in cultured hippocampal neurons. Journal of Neuroscience, 26, 11333–11341.CrossRefGoogle ScholarPubMed
Witte, A. V., Fobker, M., Gellner, R., Knecht, S. and Flöel, A. (2009). Caloric restriction improves memory in elderly humans. Proceedings of the National Academy of Sciences of the United States of America, 106, 1255–1260.CrossRefGoogle ScholarPubMed
Zhuo, J. M., Wang, H. and Praticò, D. (2011). Is hyperhomocysteinemia an Alzheimer's disease (AD) risk factor, an AD marker or neither? Trends in Pharmacological Science, 32, 562–571.CrossRefGoogle ScholarPubMed