PET imaging to assess blood-brain barrier function in alzheimers disease
Final Report Abstract
There is currently a scarcity of effective treatment options for Alzheimer’s disease (AD). A major hallmark of AD is the accumulation of senile plaques containing β-amyloid (Aβ) in the brain. Several lines of evidence suggest that reduced Aβ clearance from the brain underlies Aβ accumulation. Membrane transport proteins, such as P-glycoprotein (ABCB1) and multidrug resistance-associated protein 1 (ABCC1), which are expressed in endothelial cells of the blood-brain barrier (BBB), may contribute to excreting Aβ from brain into the blood stream. In this binational collaborative project (DACH), we used the non-invasive nuclear imaging method positron emission tomography (PET) to measure the function of ABCC1 and ABCB1 over the time course of disease progression in commonly used mouse AD models. Moreover, we tested a pharmacological approach to induce cerebral ABCC1 function as a potential therapeutic approach to reduce Aβ in the brain. PET imaging with the ABCC1 radiotracer 6-bromo-7-[11C]methylpurine failed to reveal alterations in ABCC1 function in the brains of APPPS1 mice as compared with age-matched control mice. Moreover, treatment with the antiemetic drug and potential ABCC1 inducer thiethylperazine (Torecan®) did not alter cerebral ABCC1 function in the employed mouse model. PET with the ABCB1 substrate (R)-[11C]verapamil revealed significant differences in cerebral ABCB1 function between AD and control mice at an early age of 50 days. Both in AD and control mice, there was a pronounced functional decline in cerebral ABCB1 function with increasing age, reaching a reduction of approximately 50% at the age of one year. Our data suggest that impaired ABCB1 function is present before substantial deposition of Aβ occurs indicating that ABCB1 may play a causative role in the progression of AD and that pharmacological strategies to enhance ABCB1 function at the BBB may be a useful approach to treat AD. In summary, we validated non-invasive imaging approaches to measure the function of cerebral efflux transporters, which have been implicated in brain Aβ clearance. We found significant alterations in cerebral ABCB1 function and no changes in cerebral ABCC1 function. Our imaging approaches can be readily translated to AD patients to test novel therapeutic approaches to induce transporter function at the human BBB. Moreover, PET imaging of transporter function at the BBB may prove suitable as a tool for early diagnosis of AD.
Publications
- (2015) Accumulation of murine amyloidβ mimics early Alzheimer’s disease. Brain 138, 2370-2382
Krohn M, Bracke A, Avchalumov Y, Schumacher T, Hofrichter J, Paarmann K, Fröhlich C, Lange C, Brüning T, von Bohlen und Halbach O, Pahnke J
(See online at https://doi.org/10.1093/brain/awv137) - (2015) Activation of Mitochondrial Complex II-Dependent Respiration Is Beneficial for α-Synucleinopathies. Molecular Neurobiology 53, 4728-4744
Fröhlich C, Zschiebsch K, Gröger V, Paarmann K, Steffen J, Thurm C, Schropp E-M, Brüning T, Gellerich F, Radloff M, Schwabe R, Lachmann I, Krohn M, Ibrahim S, Pahnke J
(See online at https://doi.org/10.1007/s12035-015-9399-4) - (2015) Comparative evaluation of (R)-[11C]verapamil and [11C]-N-desmethylloperamide to assess P-glycoprotein function at the mouse blood-brain barrier. European Journal of Nuclear Medicine and Molecular Imaging 42, S121
Wanek T, Mairinger S, Stanek J, Sauberer M, Filip T, Traxl A, Kuntner C, Pahnke J, Mueller M, Langer O
- (2015) Factors Governing P- Glycoprotein-Mediated Drug–Drug Interactions at the Blood–Brain Barrier Measured with Positron Emission Tomography. Molecular Pharmaceutics 12, 3214-3225
Wanek T, Römermann K, Mairinger S, Stanek J, Sauberer M, Filip T, Traxl A, Kuntner C, Pahnke J, Bauer F, Erker T, Löscher W, Müller M, Langer O
(See online at https://doi.org/10.1021/acs.molpharmaceut.5b00168) - (2016) 32nd International Austrian Winter Symposium : Zell am See, Austria. 20-23 January 2016. EJNMMI Res 6, 32
Langsteger W et al. Mairinger S, Wanek T, Krohn M, Pahnke J, Langer O
(See online at https://doi.org/10.1186/s13550-016-0168-9) - (2016) Morphometric analysis of the cerebral expression of ATP-binding cassette transporter protein ABCB1 in chronic schizophrenia: Circumscribed deficits in the habenula. Schizophrenia Research 177, 52-58
Bernstein H-G, Hildebrandt J, Dobrowolny H, Steiner J, Bogerts B, Pahnke J
(See online at https://doi.org/10.1016/j.schres.2016.02.036) - (2016) Revisiting rodent models: Octodon degus as Alzheimer’s disease model? Acta Neuropathologica Communications 4, 91
Steffen J, Krohn M, Paarmann K, Schwitlick C, Brüning T, Marreiros R, Müller-Schiffmann A, Korth C, Braun K, Pahnke J
(See online at https://doi.org/10.1186/s40478-016-0363-y) - (2017) Expression of endogenous mouse APP modulates βamyloid deposition in hAPP-transgenic mice. Acta Neuropathologica Communications 5, 49
Steffen J, Krohn M, Schwitlick C, Brüning T, Paarmann K, Pietrzik CU, Biverstål H, Jansone B, Langer O, Pahnke J
(See online at https://doi.org/10.1186/s40478-017-0448-2) - (2017) Improved method for cannula fixation for long-term intracerebral brain infusion. Journal of Neuroscience Methods 290, 145-150
Sike Á, Wengenroth J, Upīte J, Brüning T, Eiriz I, Sántha P, Biverstål H, Jansone B, Haugen HJ, Krohn M, Pahnke J
(See online at https://doi.org/10.1016/j.jneumeth.2017.07.026) - (2018) Abstracts of the 33rd International Austrian Winter Symposium : Zell am See, Austria. 24-27 January 2018. EJNMMI Res 8, 5
Binzel K et al. Zoufal V, Wanek T, Krohn M, Mairinger S, Pahnke J, Langer O
(See online at https://doi.org/10.1186/s13550-017-0354-4) - (2018) Influence of breast cancer resistance protein and P-glycoprotein on tissue distribution and excretion of Ko143 assessed with PET imaging in mice. European Journal of Pharmaceutical Sciences 115, 212-222
Mairinger S, Zoufal V, Wanek T, Traxl A, Filip T, Sauberer M, Stanek J, Kuntner C, Pahnke J, Müller M, Langer O
(See online at https://doi.org/10.1016/j.ejps.2018.01.034)
