Calpain Activation Promotes BACE1 Expression, Amyloid Precursor Protein Processing, and Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease *

  • Liang B
  • Duan B
  • Zhou X
 et al. 
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Abstract

Abnormal activation of calpain is implicated in synaptic dys-function and participates in neuronal death in Alzheimer dis-ease (AD) and other neurological disorders. Pharmacological inhibition of calpain has been shown to improve memory and synaptic transmission in the mouse model of AD. However, the role and mechanism of calpain in AD progression remain elu-sive. Here we demonstrate a role of calpain in the neuropathol-ogy in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, an established mouse model of AD. We found that overexpression of endogenous calpain inhibitor cal-pastatin (CAST) under the control of the calcium/calmodulin-dependent protein kinase II promoter in APP/PS1 mice caused a remarkable decrease of amyloid plaque burdens and prevented Tau phosphorylation and the loss of synapses. Furthermore, CAST overexpression prevented the decrease in the phosphor-ylation of the memory-related molecules CREB and ERK in the brain of APP/PS1 mice and improved spatial learning and mem-ory. Interestingly, treatment of cultured primary neurons with amyloid-␤ (A␤) peptides caused an increase in the level of ␤-site APP-cleaving enzyme 1 (BACE1), the key enzyme responsible for APP processing and A␤ production. This effect was inhibited by CAST overexpression. Consistently, overexpression of calpain in heterologous APP expressing cells up-regulated the level of BACE1 and increased A␤ production. Finally, CAST transgene prevented the increase of BACE1 in APP/PS1 mice. Thus, calpain activation plays an important role in APP processing and plaque formation, probably by regulating the expression of BACE1. Aggregation of amyloid-␤ (A␤) 3 peptides into compact plaques is a characteristic feature in the pathogenesis of Alzheimer disease (AD) (1, 2). Recently, it is suggested that soluble A␤ oligomers, in the process of aggregation, adversely affect synaptic structure and plasticity (2–9). A␤ peptides are generated in neurons by the sequential proteo-lytic cleavage of the transmembrane glycoprotein amyloid precursor protein (APP) that is cleaved initially by ␤-site APP-cleaving enzyme 1 (BACE1, also known as ␤-secretase) and subsequently by ␥-secretase, whose activity is associated with a presenilin (PS)-containing macromolecular complex (10 –12), in the transmembrane region of APP (13, 14). Thus, BACE1 has been proposed to be a therapeutic target for AD (15). Calpains are a family of calcium-activated intracellular cys-teine proteases that are involved in many physiological events including long term potentiation (16 –18) or neurotoxic insults ranging from ischemia to Alzheimer disease (19 –21). Inhibi-tion of calpain by synthetic inhibitors exerts neuroprotection in various models of brain injuries, such as ischemia or excitotox-icity-induced neuronal death (22–24). Interestingly, A␤ aggre-gation is associated with neuronal and astrocytic calcium dys-regulation (25–27). Treatment of cultured cortical neurons with A␤ oligomers caused calcium influx and subsequently cal-pain activation (21). A number of proteins have been identified as calpain sub-strates from various tissues (28). Calpain cleavage of p35, a regulatory partner of cyclin-dependent kinase 5 (Cdk5), gen-erates p25, which causes hyperactivation of Cdk5 (19, 29, 30) and causes phosphorylation of many substrates, including microtubule-associated protein Tau, resulting in the forma-tion of neurofibrillary tangles. Interestingly, induction of p25 resulted in enhanced forebrain A␤ levels before any sign of neuropathology in APP transgenic mice (31), by up-regu-lating the expression of BACE1 (32). A recent study shows that treatment with synthetic calpain inhibitor improves memory and synaptic transmission in the mouse model of AD (33). Nevertheless, it remains obscure how calpain par-ticipates in AD progression. Here we demonstrate a role for calpain in APP processing and plaque formation. We found that calpain activation increases the level of BACE1, suggesting a mechanism by which calpain promotes APP processing. These results, together with previous findings, indicate that calpain has multiple roles in AD progression, e.g. APP processing, Tau phosphorylation, synap-tic dysfunction, and neuronal death.

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Authors

  • Bin Liang

  • Bao-Yu Duan

  • Xiu-Ping Zhou

  • Jia-Xin Gong

  • Zhen-Ge Luo

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