The neuroprotective activity of the amyloid precursor protein against traumatic brain injury is mediated via the heparin binding site in residues 96-110

被引:47
作者
Corrigan, Frances [1 ]
Thornton, Emma [1 ]
Roisman, Laila C. [2 ,3 ]
Leonard, Anna V. [1 ]
Vink, Robert [1 ]
Blumbergs, Peter C. [4 ]
van den Heuvel, Corinna [1 ]
Cappai, Roberto [2 ,3 ]
机构
[1] Univ Adelaide, Sch Med Sci, Discipline Anat & Pathol, Adelaide, SA, Australia
[2] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia
[3] Univ Melbourne, Mol Sci & BioTechnol Inst Bio21, Melbourne, Vic 3010, Australia
[4] Hanson Inst, Ctr Neurol Dis, Adelaide, SA, Australia
基金
英国医学研究理事会;
关键词
NEURITE OUTGROWTH; GROWTH-FACTOR; ALZHEIMERS-DISEASE; FAMILY-MEMBERS; MICE; DOMAIN; FGF; SULFATE; APP; IMPACT;
D O I
10.1111/jnc.12391
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 sAPP alpha (the secreted ectodomain of APP generated by alpha-secretase cleavage). Two neuroprotective regions were identified in sAPP alpha, 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 sAPP alpha, represented by the sequence APP96-110, as the neuroprotective site to confer neuroprotection following TBI.
引用
收藏
页码:196 / 204
页数:9
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