Cytotoxic Fragment of Amyloid Precursor Protein Accumulates in Hippocampus after Global Forebrain Ischemia

Abstract

Summary:We developed an antibody specific to f3-amy loid precursor protein (f3APP) fragments possessing the exact amino terminus of the f3-amyloid peptide and ex amined its induction in postischemic hippocampus, In control hippocampus, this APP fragment was lightly ob served in pyramidal neurons of CA sectors and dentate granule cells, Transient forebrain ischemia enhanced ac cumulation of the APP fragment in CAl pyramidal neu rons, Seven days after the ischemia, while the APP frag ment was still observed in dentate granule cells and CA3Transient global forebrain ischemia in rodents in duces selective degeneration affecting hippocampal CAl and CA4 neurons with relative sparing of CA3 neurons and dentate granule cells. Although the de generation of CA4 neurons begins within hours after the ischemic insult, CAl neurons remain intact for up to 2 days and then degenerate (delayed neuronal death) (Kirino, 1982). The molecular mechanisms responsible for differential neuronal vulnerability to ischemic injury are incompletely understood (Schmidt-Kastner and Freund, 1991). In the previ ous study, we showed that an amyloidogenic pro cess was induced in the early phase of postischemic hippocampus (Saido et ai., 1994). Here we exam ined the detailed distribution of the cytotoxic frag ment of the (3-amyloid precursor protein «(3APP) in Received June 12, 1995; final revision received September 22. 1995; accepted March 5, 1996. Address correspondence and reprint requests to Dr. M. Yokota at Department of Neurosurgery, Hyogo College of Med icine, Mukogawa-cho I-I, Nishinomiya, Hyogo 663, Japan.Abbreviations used: AI3. l3-amyloid peptide; I3APP, l3-amyJoid precursor protein; CCA. common carotid artery; DAB, diami nobenzidine tetrahydrochloride; GFAP, glial fibrillary acidic protein; PBS, phosphate-buffered saline. 1219neurons, it disappeared in dead CAl neurons. While as trocytes did not show in any immunoreactivity through out the experiment. those in the CAl sector showed mod erate immunoreactivity 7 days after the ischemia. The APP fragment has a cytotoxic effect on cultured neurons. These results suggest that the accumulation of the cyto toxic APP fragment in CAl neurons may play a role in the development of delayed neuronal death after the ischemic insult.

Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses

“…Ischemia, hypoglycemia, and traumatic brain injury, a condition that has been shown to put neurons under metabolic stress (Xiong et al, 1997), all up-regulate A␤PP and its mRNA in animal models and culture systems (Hall et al, 1995;Jendroska et al, 1995;Yokota et al, 1996;Shi et al, 1997;Murakami et al, 1998). Not only does energy deficiency and Ca(II) dysregulation promote A␤PP expression, they also route the metabolism of A␤PP from the nonamyloidogenic to the amyloidogenic pathway.…”

Hypoxic Enhancement of Quantal Catecholamine Secretion

“…Most important, we have demonstrated that reduced O 2 levels alone can induce formation of A␤P-mediated Ca 2ϩ influx. As described in the Introduction, A␤Ps are the cleavage products derived from amyloid precursor protein (5,6), and levels of this precursor have been shown to increase following ischemia (9,10). The enhanced Ca 2ϩ influx reported here may therefore be an important contributory factor to the increased incidence of dementias and amyloid deposition following cerebral ischemia, leading to neurotoxicity through excessive transmitter release.…”

“…Since APP is generally perceived to be neuroprotective, this increased expression of APP can be considered a defense mechanism against ischemia. However, increased APP levels seen in ischemia would also permit increased formation of A␤Ps, which cause neuronal damage and death (4); and indeed, A␤P production is increased following both mild and severe ischemia (9,10). Thus, a clear link exists between ischemic insult and elevation of damaging A␤P levels.…”

Alzheimer's Factors in Ischemic Brain Injury

“…Animals after focal and global ischemic brain injury with a survival time up to 1 year presented increased brain immunoreactivity to the -amyloid peptide and as well as to the N-and C-terminal of amyloid precursor protein. The staining was observed extracellularly and intracellularly (Pluta et al, 1994b;Hall et al, 1995;Tomimoto et al, 1995;Horsburgh, Nicoll, 1996a;Ishimaru et al, 1996a;Yokota et al, 1996;Pluta et al, 1997b;Pluta et al, 1998b;Lin et al, 1999;Pluta 2000;Lin et al, 2001;Sinigaglia-Coimbra et al, 2002;Fujioka et al, 2003;. Different fragments of amyloid precursor protein were noted in astrocytes, neurons, oligodendrocytes, and microglia (Banati et al, 1995;Palacios et al, 1995;Pluta et al, 1997b;Nihashi et al, 2001;Pluta, 2002a;Pluta2002b;Badan et al, 2003;Badan et al, 2004).…”

“…Multifocal and widespread different kinds of amyloid plaques were observed mainly in the ischemic hippocampus, brain and entorhinal cortex, and corpus callosum, and subventriculary (Pluta et al, 1994b;Pluta et al, 1997b;Pluta et al, 1998b;Pluta 2000;Pluta 2003;Pluta 2005;Pluta et al, 2009;Pluta et al, 2010). The accumulation of the -amyloid peptide in astrocytes and the C-terminal of amyloid precursor protein in ischemic neurons underline the likely importance of these two proteins in ischemic brain injury cascade of degeneration (Pluta et al, 1994b;Yokota et al, 1996;Pluta 2002b;Badan et al, 2003;Badan et al, 2004). Moreover, the above parts of precursor deposits suggest that these fragments of precursor may initiate synaptic pathology and finally promote retrograde neuronal death after ischemic injury (Oster-Granite et al, 1996).…”