Accelerated accumulation of N‐ and C‐terminal βAPP fragments and delayed recovery of microtubule‐associated protein 1B expression following stroke in aged rats

Abstract

The age-related decline in plasticity of the brain may be one factor underlying poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity in old age could be the result of an altered temporal relationship between factors promoting brain plasticity [microtubule-associated protein 1B (MAP1B)] and neurotoxic factors such as C-terminal betaAPP. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14 and 28 days after surgery. At the indicated timepoints, brains were removed and immunostained for C- and N-terminal betaAPP and MAP1B. At 2 weeks poststroke, we found an age-related increase in the amount of the C-terminal fragment of betaAPP in the peri-infarcted area and the infarct core as well as an early, vigorous incorporation of N-terminal betaAPP into the developing astroglial scar. The recovery of the plasticity-associated protein MAP1B following stroke was delayed in both age groups and became prominent between days 14 and 28. As aged rats showed diminished functional recovery compared with young rats, these results suggest that the accumulation of C-terminal betaAPP, together with the early incorporation of N-terminal betaAPP into the glial scar, may over-ride the beneficial role of plasticity factors such as MAP1B.

Stroke-Induced Subventricular Zone Proliferation is Promoted by Tumor Necrosis Factor-α-Converting Enzyme Protease Activity

“…Specifically, evidence suggests that accumulation of C-and N-terminal fragments from b-secretase cleavage of APP interfere with plasticity-related factors such as MAP1B (Badan et al, 2004). It has therefore been surmised that overexpression of APP combined with enhanced amyloidogenic processing may be a factor in neurodegeneration after stroke (Koistinaho and Koistinaho, 2005).…”

Alzheimer's Factors in Ischemic Brain Injury

“…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).…”

“…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). Animals with long survival after ischemic brain injury from 0.5 to 1 year showed pathological brain staining only to the -amyloid peptide and to the C-terminal of amyloid precursor protein (Pluta et al, 1998b;Pluta 2000).…”

“…Animals with long survival after ischemic brain injury from 0.5 to 1 year showed pathological brain staining only to the -amyloid peptide and to the C-terminal of amyloid precursor protein (Pluta et al, 1998b;Pluta 2000). The reactive astrocytes with deposition of different fragments of amyloid precursor protein might be involved in the development of glial scar (Nihashi et al, 2001;Pluta 2002a;Pluta 2002b;Badan et al, 2003;Badan et al, 2004). Reactive astrocytic cells with pathological level of -amyloid peptide deposition might be involved in pathological repair of host tissue after ischemic brain injury including astrocytes death (Pluta et al, 1994b;Pluta 2002b;WyssCoray et al, 2003;Takuma et al, 2004).…”

“…The relationship between brain ischemic injury dementia and Alzheimer's disease type dementia is recently much debated. The mechanisms of the progressive cognitive decline after ischemic brain injury are not yet clear but animal investigations have demonstrated an increase in expression and processing of amyloid precursor protein to -amyloid peptide (Pluta et al, 1994b;Pluta et al, 1997b;Pluta et al, 1997c;Pluta et al, 1998b;Lin et al, 1999;Shi et al, 2000;Lin et al, 2001;Badan et al, 2004;Pluta et al, 2009) and an increase in the phosphorylation of tau protein (Dewar, Dawson 1995;Wen et al, 2004b;Wen et al, 2004c, Wen et al, 2007. Moreover, the common mechanism that links progressive cognitive decline after ischemic brain injury and during Alzheimer's disease is neuroinflammation (Koistinaho et al, 2002), which can cause gradual neurodegeneration during prolonged face of injury.…”