Focal cerebral ischemia in rats alters APP processing and expression of Aβ peptide degrading enzymes in the thalamus

Hiltunen, Mikko; Mäkinen, Petra; Peräniemi, Sirpa; Sivenius, Juhani; Groen, Thomas van; Jolkkonen, Jukka

doi:10.1016/j.nbd.2009.04.009

Cited by 58 publications

(63 citation statements)

References 36 publications

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“…Extracellular Aβ deposits are accompanied by accumulated autophagosomes in the neurons of AD patients and presenilin-1/ APP mice, indicating the potential relationship between autophagy and Aβ deposits. 19,20,37,38 Consistent with previous studies, 21,39 we found that cerebral ischemia led to Aβ deposits in the ipsilateral thalamus. Thus, we cannot rule out the possibility that inhibition of autophagy may protect against Aβ-induced neuronal damage.…”

Section: Do Not Distributesupporting

confidence: 87%

Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction

Xing

Zhang²,

Li³

et al. 2012

Autophagy

138

112

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Key words: autophagy, Beclin 1, 3-methyladenine, amyloid β, c-secretase inhibitor, cerebral infarction, thalamus, secondary degeneration-S-phenylglycine t-butyl ester; LC3, microtubule-associated protein 1 light chain 3A; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; RHRSP, stroke-prone renovascular hypertensive rats; shRNA, short-hairpin RNA Cerebral infarction can cause secondary degeneration of thalamus and delay functional recovery. However, the mechanisms underlying secondary degeneration are unclear. The present study aimed to determine the occurrence and contribution of autophagy to thalamic degeneration after cerebral infarction. Focal cerebral infarction was induced by distal middle cerebral artery occlusion (MCAO). Autophagic activation, Beclin 1 expression and amyloid b (Ab) deposits were determined by immunofluorescence, immunoblot and electron microscopy. Secondary damage to thalamus was assessed with Nissl staining and immunofluorescence analysis. Apoptosis was determined using TUNEL staining. The contribution of autophagy to the secondary damage was evaluated by shRNA-mediated downregulation of Beclin 1 and the autophagic inhibitor, 3-methyladenine (3-MA). The potential role of Ab in autophagic activation was determined with N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The results showed that the conversion of LC3-II, the formation of autophagosomes, and the levels of activated cathepsin B and Beclin 1 were significantly increased in the ipsilateral thalamus at 7 and 14 d after MCAO (p , 0.05 or 0.01). Both Beclin 1 knockdown and 3-MA treatment significantly reduced LC3-II conversion and autophagosome formation, which were accompanied by obvious decreases in neuronal loss, gliosis and apoptosis in the ipsilateral thalamus (p , 0.05 or 0.01). Additionally, DAPT treatment markedly reduced Ab deposits, which coincided with decreases in LC3-II conversion and autophagosome formation (p , 0.01). These results suggest that inhibition of autophagy by Beclin 1 knockdown can attenuate the secondary thalamic damage after focal cerebral infarction. Furthermore, Ab deposits may be involved in the activation of autophagy.

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Section: Do Not Distributesupporting

confidence: 87%

Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction

Xing

Zhang²,

Li³

et al. 2012

Autophagy

138

112

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“…traumatic brain injury (21), oxidative stress (22), and cerebral ischemia (11,23,24). Recently, it was demonstrated that GGA3 is an adaptor protein responsible for sorting of BACE to the lysosome for degradation (11).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of Seladin-1 Increases BACE1 Levels and Activity through Enhanced GGA3 Depletion during Apoptosis

Sarajärvi

Haapasalo

Viswanathan

et al. 2009

Journal of Biological Chemistry

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Seladin-1 is a neuroprotective protein selectively downregulated in brain regions affected in Alzheimer disease (AD).Seladin-1 protects cells against ␤-amyloid (A␤) peptide 42-and oxidative stress-induced apoptosis activated by caspase-3, a key mediator of apoptosis. Here, we have employed RNA interference to assess the molecular effects of seladin-1 down-regulation on the ␤-secretase (BACE1) function and ␤-amyloid precursor protein (APP) processing in SH-SY5Y human neuroblastoma cells in both normal and apoptotic conditions. Our results show that ϳ60% reduction in seladin-1 protein levels, resembling the decrease observed in AD brain, did not significantly affect APP processing or A␤ secretion in normal growth conditions. However, under apoptosis, seladin-1 small interfering RNA (siRNA)-transfected cells showed increased caspase-3 activity on average by 2-fold when compared with control siRNA-transfected cells. Increased caspase-3 activity coincided with a significant depletion of the BACE1-sorting protein, GGA3 (Golgi-localized ␥-ear-containing ADP-ribosylation factor-binding protein), and subsequently augmented BACE1 protein levels and activity. Augmented BACE1 activity in turn correlated with the enhanced ␤-amyloidogenic processing of APP and ultimately increased A␤ production. These adverse changes associated with decreased cell viability in seladin-1 siRNAtransfected cells under apoptosis. No changes in GGA3 or BACE1 levels were found after seladin-1 knockdown in normal growth conditions. Collectively, our results suggest that under stress conditions, reduced seladin-1 expression results in enhanced GGA3 depletion, which further leads to augmented post-translational stabilization of BACE1 and increased ␤-amyloidogenic processing of APP. These mechanistic findings related to seladin-1 down-regulation are important in the context of AD as the oxidative stress-induced apoptosis plays a key role in the disease pathogenesis. Alzheimer disease (AD)2 is the most common neurodegenerative disorder leading to dementia. It is neuropathologically characterized by extracellular amyloid plaques as well as intraneuronal neurofibrillary tangles, composed of ␤-amyloid peptide (A␤) and hyper-phosphorylated Tau, respectively. A␤ is generated from the ␤-amyloid precursor protein (APP) after sequential cleavages by ␤-and ␥-secretases (1). Importantly, mutations in APP and PSEN1 and -2 genes have been shown to increase the production of the 42-amino acid-long A␤42 and to cause the familial autosomal dominant form of AD. Based on this notion, it has been proposed that aberrant metabolism of APP is the initiating event in AD pathogenesis, which is followed by other adverse events, such as inflammation, oxidative stress, and neurofibrillary tangle formation (2). Recently, this model was challenged by a dual pathway hypothesis, which proposed that A␤ and Tau can actually be linked by separate mechanisms driven by common upstream initiators, such as apolipoprotein E (apoE) or glycogen synthase kinase-3 (3). Therefore, considering th...

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“…These may trigger angiogenesis and chronic hyperperfusion to support the removal of necrotic brain tissue (Manoonkitiwongsa et al, 2001) and aid repair processes. To what extent CBF recovery and angiogenesis promote behavioral improvement after cerebral ischemia is difficult to assess due to the complex pathology in the thalamus (Hiltunen et al, 2009) and multiple mechanisms underlying functional recovery (Witte, 1998). However, there was a temporal association between CBF in the ipsilateral thalamus and cylinder data, that is, initial hypoperfusion and severe sensorimotor impairment was followed by hyperperfusion and recovery of the forelimb function.…”

Section: Functional and Therapeutic Implicationsmentioning

confidence: 99%

“…Because of its synaptic connections to the cortex, the thalamus is affected by focal cerebral ischemia (Nakane et al, 2002). In addition to delayed retrograde degeneration of thalamocortical neurons (Ross and Ebner, 1990), thalamic pathology involves activation of inflammatory processes (Block et al, 2005), impairment of calcium homeostasis (Watanabe et al, 1998;Mäkinen et al, 2008), and complex alterations in amyloid precursor protein processing leading eventually to amyloid-b deposition (van Groen et al, 2005;Hiltunen et al, 2009). The reliability of this system is essential for sensorimotor recovery after stroke (Staines et al, 2002), yet its hemodynamic response after focal cerebral ischemia in rats has, to our knowledge, not been studied.…”

Section: Introductionmentioning

confidence: 99%

Chronic Hyperperfusion and Angiogenesis Follow Subacute Hypoperfusion in the Thalamus of Rats with Focal Cerebral Ischemia

Hayward

Yanev

Haapasalo

et al. 2010

J Cereb Blood Flow Metab

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Cerebral blood flow (CBF) is disrupted after focal ischemia in rats. We examined long-term hemodynamic and cerebrovascular changes in the rat thalamus after focal cerebral ischemia. Cerebral blood flow quantified by arterial spin labeling magnetic resonance imaging was decreased in the ipsilateral and contralateral thalamus 2 days after cerebral ischemia. Partial thalamic CBF recovery occurred by day 7, then the ipsilateral thalamus was chronically hyperperfused at 30 days and 3 months compared with its contralateral side. This contrasted with permanent hypoperfusion in the ipsilateral cortex. Angiogenesis was indicated by endothelial cell (RECA-1) immunohistochemistry that showed increased blood vessel branching in the ipsilateral thalamus at the end of the 3-month follow-up. Only transient thalamic IgG extravasation was observed, indicating that the blood-brain barrier was intact after day 2. Angiogenesis was preceded by transiently altered expression levels of cadherin family adhesion molecules, cadherin-7, protocadherin-1, and protocadherin-17. In conclusion, thalamic pathology after focal cerebral ischemia involved longterm hemodynamic changes and angiogenesis preceded by altered expression of vascular adhesion factors. Postischemic angiogenesis in the thalamus represents a novel type of remote plasticity, which may support removal of necrotic brain tissue and aid functional recovery.

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Focal cerebral ischemia in rats alters APP processing and expression of Aβ peptide degrading enzymes in the thalamus

Cited by 58 publications

References 36 publications

Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction

Beclin 1 knockdown inhibits autophagic activation and prevents the secondary neurodegenerative damage in the ipsilateral thalamus following focal cerebral infarction

Down-regulation of Seladin-1 Increases BACE1 Levels and Activity through Enhanced GGA3 Depletion during Apoptosis

Chronic Hyperperfusion and Angiogenesis Follow Subacute Hypoperfusion in the Thalamus of Rats with Focal Cerebral Ischemia

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