The amyloid ?-protein precursor (A?PP) is highly expressed in brain although its physiological functions remain poorly understood. Many functional domains have been identified on secreted forms of A?PP proteins that could participate in variety of neuroprotective activities ranging from proteinase inhibition to ligand binding to cytoprotection. For example, it is known that shortly following stroke there is a marked increase in the expression of A?PP suggesting that it may serve a protective function in response to this acute deleterious event. During the previous funding period we investigated the role of the Kunitz proteinase inhibitor (KPI) domain, contained in the 751/770 isoforms of secreted A?PP (sA?PP), in regulating thrombosis that occurs during the initial stages of cerebral vascular injury. Indeed, for the first time we unequivocally demonstrated that the KPI activity of sA?PP-751/770 limits the extent of thrombosis associated with in vivo models of carotid artery thrombosis, cerebral hemorrhage, and focal cerebral ischemia. Despite these significant findings regarding in vivo functions of the KPI domain of sA?PP other important activities are likely associated with other biologically active domains present on sA?PP proteins in response to acute cerebral injuries including ischemic and hemorrhagic stroke and chronic disorders such as Alzheimer's disease (AD). Specifically, the N-terminal region of A?PP (A?PP18-119), upstream from the KPI domain, is a highly structured, naturally occurring fragment that possesses potential neuroprotective functions that could influence the consequences of different acute and chronic cerebral insults. Thus, the overall hypothesis that forms the basis of this competitive renewal is that the N-terminal region A?P18-119 is neuroprotective in response to acute and chronic cerebral injuries. Whereas previously we focused on the cerebral function of the KPI domain of sA?PP the broad objective of this competitive renewal is to investigate the functions of the upstream, N-terminal region of sA?PP in vivo in the brain. We plan to implement a combination of in vivo studies to investigate if the N-terminus of A?PP provides protection from the deleterious consequences of acute cerebral vascular injuries including ischemic and hemorrhagic stroke and more chronic cerebral insults associated with AD-like amyloid pathologies. Our studies will utilize novel gene mutation knock in and transgenic mouse lines related to A?PP activities subjected to experimental models of acute and chronic cerebral insults and evaluated for short-term and long-term imaging, pathological, and behavioral outcomes. Completion of these studies will yield new insight into biological activities and potential neuroprotective functions of the N-terminus of A?PP in these injury situations. Finally, A?PP18-119, and fragments thereof, could provide the basis of therapeutic agents to ameliorate the deleterious consequences of acute ischemic and hemorrhagic stroke as well as more chronic amyloid pathologies associated with AD and related disorders.
Acute cerebral injury such as stroke and chronic cerebral injury such as Alzheimer's disease are leading causes of death and disability in this country. Endogenous neuroprotective brain factors that influence the severity of short-term and long-term consequences of cerebral injury still remain to be better defined. The purpose of this proposal is to investigate the neuroprotective properties of the N-terminal region of the amyloid?-protein precursor in acute and chronic cerebral injuries.
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