Temporal Dynamics of Degenerative and Regenerative Events Associated with Cerebral Ischemia in Aged Rats

Abstract

Background and Purpose: The age-related decline in plasticity of the brain may be one factor underlying the poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity could be the result of an age-related reduction in the upregulation of factors promoting brain plasticity (microtubule-associated protein 1B [MAP1B], β-amyloid precursor protein [βAPP]), and an age-related increase in glial reactivity and the accumulation of Aβ, a proteolytic cleavage product of βAPP with neurotoxic properties. Methods: 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 3, 7, 14 and 28 days after surgery. At the indicated time points, brains were removed and immunostained for glial cells. Aβ, as well as the markers of brain plasticity, βAPP and MAP1B. Results: Histologically, in young rats there was a gradual activation of both microglia and astrocytes that peaked by days 14–28 with the formation of a glial scar. In contrast, aged rats showed an accelerated astrocytic and microglial reaction that peaked in the first week after stroke. The expression patterns of a growth-associated phenotype of βAPP as well as with MAP1B accumulation in varicosities along axons in cortical areas affected by stroke peaked between days 14 and 28 in young animals. In aged rats their expression was both delayed (28 days) and reduced. In addition the carboxy terminal fragment of βAPP steadily accumulated over time and reached a maximum by day 14 in aged rats as compared to 28 days in young rats. Conclusions: These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats in conjunction with a late and limited upregulation of neuronal plasticity proteins as well as a diminished neurogenesis potential lead to the prevalence of scar tissue that impedes functional recovery from stroke.

N-cadherin mediates nitric oxide-induced neurogenesis in young and retired breeder neurospheres

“…However, an age-related increase in glial reactivity causes reduced brain plasticity (Badan et al, 2003b). GFAP plays an important role in age-related deficits in learning and memory (Wu et al, 2005).…”

“…In addition, accelerated glial reactivity in aged rats also correlates with reduced functional recovery after stroke (Badan et al, 2003a). Glial reactivity increases with age, which coincides with the accumulation of beta-amyloid peptide (Abeta) (Badan et al, 2003b). Abeta can evoke reactive gliosis in response to neurodegeneration (Nichols, 1999), whereas, the nitric oxide (NO)/cGMP pathway opposes the effects of Abeta in the regulation of vasoconstriction (Paris et al, 1999).…”

Alzheimer's Factors in Ischemic Brain Injury

“…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).…”

Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model

“…The results from the young animals confirm the ischemia-dependent decrease in GFAP expression that was previously described 48 h after reperfusion in a 4VO model of global ischemia in young Wistar rats (Zhang et al 2007). Several studies provide evidence that aging brain reacts stronger to I/R with an early inflammation response (Badan et al 2003;Popa-Wagner et al 2007;Buga et al 2013), and it has been reported that aged Sprague-Dawley rats present an early glial scar in an MCAO model (Popa-Wagner et al 2006). Also, GFAP reactivity in humans has been described to depend on the age of patient (Dziewulska 1997).…”