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Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774. PubMed.
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University of Oslo
Congratulations!
Very nice study showing the effects of reduced Aβ clearance in AD patients. Even in a small cohort and with a limited time for analysis, the effects are nicely stated.
The precise mechanism underlying these findings have now to be described and will represent a new avenue for treatment and diagnostics.
Previous publications highlighted important effects of ABC transporters. The following questions arise:
1. Which active transporters play a major role?
2. Where are these transporters located?
3. Which brain barriers facilitate this action...blood-brain and blood-plexus choroideus barrier?
4. Where are these excreting transporters located in plasma membrane (endothelia, ependyma)...apical, basolateral?
5. Is there a chain of actions of various Aβ-excreting transporters at each membrane/barrier? Can we find a co-transported, new, indirect disease biomarker or define an in vivo assay to describe ABC transporter function in patients?
6. What is the risk of the huge number of inhibiting drugs in the market? Long-term treatment with such drugs reduces ABC transporter function and perhaps also Aβ clearance from the brain. (e.g., β-blockers, calcium antagonists, cytostatica).
7. Is it a general mechanism? Can we set up a model to describe these clearance effects and calculate the risk correlated specifically to reduced transporter action? To what extent do we have to reduce ABC transporter function to cause accelerated amyloid pathology in model organisms and patients (5 percent, 25 percent or even 50 percent)? Our own findings point to less than 20 percent in mice!
8. What are the structural consensi for the selectivity of specific ABC transporters for Aβ?
9. Do these findings explain the unsatisfying results of the immunization studies? Clearance of plaques but stuck low molecular mass, toxic amyloid moieties intraparenchymally in the brain due to a vast overload of the remaining clearance capacity.
10. Can we activate Aβ-exporting ABC transporters specifically for treatment?
11. Is it common regulation/mechanism that explains a subset of age-dependent neurodegenerative, sporadic diseases (AD, PD, ALS, CJD, and so on)? Aging leading to reduced mitochondrial function/ATP levels, leading to vascular changes, leading to abrogated ABC transporter/microglia action, leading to reduction of clearance/degradation of toxic peptides....
12. ABC transporters play an important role for stem cell homing and differentiation!
13. The ABCB1 transporter has also been shown to be involved in 11C-Verapamil accumulation in Parkinson's patients in the Substantia nigra. Are ABC transporters necessary for α-synuclein clearance? How about other proteinopathies?
14. The recent findings that peripherally injected Aβ results in intracerebral Aβ accumulation may also be explained by reduced ABC transporter excretion (plug) or pathological Aβ-binding due to increased intravascular amyloid. Are ABC transporters “strain” specific?
References:
Pahnke J, Walker LC, Scheffler K, Krohn M. Alzheimer's disease and blood-brain barrier function-Why have anti-beta-amyloid therapies failed to prevent dementia progression?. Neurosci Biobehav Rev. 2009 Jul;33(7):1099-108. PubMed.
Vogelgesang S, Warzok RW, Cascorbi I, Kunert-Keil C, Schroeder E, Kroemer HK, Siegmund W, Walker LC, Pahnke J. The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2004 May;1(2):121-5. PubMed.
Islam MO, Kanemura Y, Tajria J, Mori H, Kobayashi S, Shofuda T, Miyake J, Hara M, Yamasaki M, Okano H. Characterization of ABC transporter ABCB1 expressed in human neural stem/progenitor cells. FEBS Lett. 2005 Jul 4;579(17):3473-80. PubMed.
Eisele YS, Obermüller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Walker LC, Staufenbiel M, Heikenwalder M, Jucker M. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.
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