Abeta plaques (extracellular deposits of misfolded proteins containing toxic beta-Amyloid peptides) are a hallmark and translational biomarker of Alzheimer’s disease (AD).
These microscopic structures (5-30 micrometers) are scattered throughout hippocampus and cortex, both in AD patients and in animal models of AD.
In transgenic mouse models of AD, Abeta plaques can be quantitatively measured n vivo using systemic administration of fluorescent tracers such as Methoxy-X04 (see the Figure, top panel).
Neurotar’s in vivo two-photon microscopy assays allow tracing longitudinally individual Abeta plaques, detecting appearance of new plaques, quantifying their grows as disease progresses. We measure shrinking/disappearance of existing plaques upon treatment with drug candidates (both small molecules and biologics such as Abeta-targeting antibodies). Each plaque is identified and measured repeatedly in multiple imaging sessions, thus boosting the statistical power as individual plaques are used as their own pre-treatment control.
Pharmacodynamic effects of drugs on Abeta plaque size and number can be measured simultaneously with Pharmacokinetics of biologics (e.g., red-labelled antibodies) as they penetrate through BBB, accumulate in brain parenchyma, co-localize with green-labelled plaques, and gradually re-distribute from the plaque’s periphery into their dense core.
- 2-3 groups (1 placebo, 1-2 compounds)
- 4 imaging sessions (0 h, 24 h, 72 h, 144 h)
- 1-3 imaging areas per animal
- Plaque number and size is measured for individual Abeta plaques (both pre-existing and newly-formed)
Options and extensions
- Intrathecal delivery
- Viral expression of fluorescent proteins to label neurons
- Colocalization of plaques with blood vessels
- Gureviciene I, Gurevicius K, Mugantseva E, Kislin M, Khiroug L, Tanila H. (2017) Amyloid Plaques Show Binding Capacity of Exogenous Injected Amyloid-β. J Alzheimers Dis. 55(1):147-157. IOS press
Other relevant publications:
- Hefendehl JK, Wegenast-Braun BM, Liebig C, Eicke D, Milford D, Calhoun ME, Kohsaka S, Eichner M, Jucker M. (2011) Long-term in vivo imaging of β-amyloid plaque appearance and growth in a mouse model of cerebral β-amyloidosis. J Neurosci 31:624 – 9 10.1523/JNEUROSCI.5147-10.2011
- Baik, S. H., Kang, S., Son, S. M. and Mook-Jung, I. (2016), Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer’s disease mouse model. Glia, 64: 2274–2290. 10.1002/glia.23074
- Hefendehl JK, LeDue J, Ko RWY, Mahler J, Murphy TH, MacVicar BA (2016) Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging. Nat Commun 17. doi:10.1038/ncomms13441 10.1038/ncomms13441
Mouse lines provided by Clients or third-party CROs