Cerebral ischemia leads to a transient upregulation and accumulation of β-amyloid precursor protein (APP). For example, APP staining and expression are detected in the subcortical white matter and adjacent to the boundary of the ischemic lesion in the grey matter following transient occlusion of the middle cerebral artery (MCAO). Previous studies, however, have used only short survival periods ranging from days to weeks. The aim of the present study was to assess possible long-term accumulation of APP and Aβ during a 9-month follow-up in rats subjected to transient MCAO. Male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 hours. Sensorimotoric outcome was assessed using a tapered/ledged beam-walking task following operation. The distribution of APP and Aβ was examined immunohistochemically at 1 week, 1 month, and 9 months after MCAO. Histologic analysis revealed severe corticostriatal damage in all MCAO rats. MCAO caused a long-lasting deficit in forelimb and hindlimb function assessed using the beam-walking test. In MCAO rats that survived 1 week, APP staining was present around the ischemic area, in the corpus callosum in crossing axons, in descending axons leaving the lesioned area, and in the terminal zone of these axons in the thalamus. There was staining for both N- and C-terminal APP. Similarly, there was positive Aβ staining in all of these areas. After 1 month survival, some N- and C-terminal APP staining was present around the ischemic area, but most APP was present at the terminal zone of the deafferented axons in the thalamus. Most N-terminal APP was extracellular, in contrast to the C-terminal APP, which was predominantly intracellular. Aβ was stained in a similar pattern in these areas; most Aβ was extracellular, but some staining was present in axons. At 9 months following the MCAO, APP staining was not present around the lesioned area, in the corpus callosum, or in descending axons leaving the lesioned area. In the thalamus in the terminal zone of the deafferented corticothalamic axons, however, there were large, dense deposits, that resembled plaques and consisted of N-terminal APP. These deposits were also positively stained for Aβ, but not for C-terminal APP. In conclusion, C- and N-terminal APP and Aβ staining was present in areas adjacent to the infarct, the corpus callosum, and the thalamus for 1 week after MCAO. The staining of these proteins later disappeared from the cortical areas and white matter, but was still evident in the thalamus 9 months after MCAO. The N-terminal APP and Aβ staining in the thalamus was diffuse acutely after the infarct, but accumulated, leading to dense plaque-like deposits in the ventroposterior lateral and ventroposterior medial nuclei, a finding that has not been reported previously. It is suggested that following focal cerebral ischemia APP and Aβ are transported through corticothalamic axons and secreted at terminals where they form diffuse deposits, which over time develop into plaque-like structures.
