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|Title:||The neuroprotective activity of the amyloid precursor protein against traumatic brain injury is mediated via the heparin binding site in residues 96-110|
Van Den Heuvel, C.
|Citation:||Journal of Neurochemistry, 2014; 128(1):196-204|
|Frances Corrigan, Emma Thornton, Laila C. Roisman, Anna V. Leonard, Robert Vink, Peter C. Blumbergs, Corinna van den Heuvel and Roberto Cappai|
|Abstract:||We have previously shown that following traumatic brain injury (TBI) the presence of the amyloid precursor protein (APP) may be neuroprotective. APP knockout mice have increased neuronal death and worse cognitive and motor outcomes following TBI, which is rescued by treatment with exogenous sAPPα (the secreted ectodomain of APP generated by α-secretase cleavage). Two neuroprotective regions were identified in sAPPα, the N and C-terminal domains D1 and D6a/E2 respectively. As both D1 and D6a/E2 contain heparin binding activity it was hypothesized that this is responsible for the neuroprotective activity. In this study, we focused on the heparin binding site, encompassed by residues 96-110 in D1, which has previously been shown to have neurotrophic properties. We found that treatment with APP96-110 rescued motor and cognitive deficits in APP−/− mice following focal TBI. APP96-110 also provided neuroprotection in Sprague–Dawley rats following diffuse TBI. Treatment with APP96-110 significantly improved functional outcome as well as preserve histological cellular morphology in APP−/− mice following focal controlled cortical impact injury. Furthermore, following administration of APP96-110 in rats after diffuse impact acceleration TBI, motor and cognitive outcomes were significantly improved and axonal injury reduced. These data define the heparin binding site in the D1 domain of sAPPα, represented by the sequence APP96-110, as the neuroprotective site to confer neuroprotection following TBI.|
|Keywords:||Animals; Mice, Inbred C57BL; Mice, Knockout; Mice; Rats; Rats, Sprague-Dawley; Brain Injuries; Heparin; Amyloid beta-Protein Precursor; Neuroprotective Agents; Random Allocation; Binding Sites; Amino Acid Sequence; Protein Structure, Tertiary; Molecular Sequence Data; Male; Mice, 129 Strain|
|Description:||Article first published online: 28 AUG 2013|
|Rights:||© 2013 International Society for Neurochemistry|
|Appears in Collections:||Medical Sciences publications|
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