Alzheimer’s disease patients show reduced rates of Aβ clearance, yet normal Aβ production, according to a study posted online in ScienceXpress today. Senior investigator Randall Bateman of Washington University School of Medicine, St. Louis, Missouri, reported these data in July at the International Conference on Alzheimer’s Disease in Honolulu, Hawaii (ARF related conference story).

Using metabolic labeling and other analytical techniques, first author Kwasi Mawuenyega and colleagues measured real-time Aβ turnover in the cerebrospinal fluid of 12 late-onset AD patients and 12 age-matched controls over a 36-hour period. Both groups produced CNS Aβ at similar rates, around 6.8 percent of the total per hour. However, while healthy elderly cleared Aβ40 and Aβ42 at rates of 7.0 and 7.6 percent per hour, respectively, AD patients got rid of their Aβ about 30 percent more slowly. Estimates based on this clearance impairment “suggest that brain Aβ accumulates over approximately 10 years in AD,” the authors wrote.

In addition to impaired CNS Aβ clearance, the AD group had lower concentrations of CSF Aβ42. However, the relationship between these two measures is not fully understood, the authors point out. There may be “more than one pool of Aβ in the CSF, undetected pools of Aβ in CSF by ELISA (e.g., oligomers), or a combined increase in Aβ production with impaired efflux from parenchyma to CSF,” they noted.—Esther Landhuis

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  1. 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:

    . 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.

    . 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.

    . Characterization of ABC transporter ABCB1 expressed in human neural stem/progenitor cells. FEBS Lett. 2005 Jul 4;579(17):3473-80. PubMed.

    . Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.

References

News Citations

  1. Honolulu: Wake-Up Call—Aβ Clearance, Not Production, Awry in AD

Further Reading

Primary Papers

  1. . Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774. PubMed.