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

Abstract

Abnormal activation of calpain is implicated in synaptic dysfunction and participates in neuronal death in Alzheimer disease (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 elusive. Here we demonstrate a role of calpain in the neuropathology 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 calpastatin (CAST) under the control of the calcium/calmodulindependent 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 phosphorylation of the memory-related molecules CREB and ERK in the brain of APP/PS1 mice and improved spatial learning and memory. 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 proteolytic 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 cysteine 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). Inhibition of calpain by synthetic inhibitors exerts neuroprotection in various models of brain injuries, such as ischemia or excitotoxicity-induced neuronal death (22-24). Interestingly, A␤ aggregation is associated with neuronal and astrocytic calcium dysregulation (25-27). Treatment of cultured cortical neurons with A␤ oligomers caused calcium influx and subsequently calpain activation (21).A number of proteins hav...

Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores Normal Lifespan in Tau P301L Mice

“…1 D, P, p Ͻ 0.05, Student's t test), and levels of the specific calpain-cleaved 150 kDa spectrin breakdown product Rao et al, 2008;Liang et al, 2010;Higuchi et al, 2012) were also significantly increased ( Fig. 1 E, P, p Ͻ 0.05, Student's t test).…”

“…Altered activities of cdk5, ERK1/2, GSK3␤, and PP2A (phosphatase 2A) contribute to pathological tau hyperphosphorylation and have disruptive effects on neuronal cell function, leading to neurodegeneration (Iqbal et al, 2010). Tau can also form neurotoxic oligomers which affect synaptic receptors or membranes Lasagna-Reeves et al, 2011a;Henkins et al, 2012;Ward et al, 2012) by disrupting vesicular trafficking or function, and may propagate toxicity transneuronally (de Calignon et al, 2012;Liu et al, 2012;Walker et al, 2013).…”

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…Multiple mechanisms are recently proposed to mediate the upregulation of BACE1 associated with AD. Those include the increased phosphorylation of the translation initiation factor eIF2a Devi and Ohno, 2010b;O'Connor et al, 2008), caspase-3-dependent inactivation of GGA3 leading to decreased lysosomal degradation of BACE1 (Sarajarvi et al, 2009;Tesco et al, 2007), changes in microRNA expression profiles (Hebert et al, 2008;Wang et al, 2008), p25/cyclin-dependent kinase 5 pathways (Cruz et al, 2006;Wen et al, 2008), calpain activation (Liang et al, 2010), the receptor for advanced glycation end products (RAGE) (Cho et al, 2009;Guglielmotto et al, 2010), and oxidative stress or related signals such as nuclear factor-kB, c-Jun N-terminal kinase, and p38 MAPK (Chen et al, 2011;Chen et al, 2008;Coma et al, 2008;Xiong et al, 2007). Further study will be needed to determine the molecular pathways by which activation of BDNF-TrkB signaling may counteract the BACE1 elevation in 5XFAD mice.…”

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…One of the culprits of AD is the overactivation of calpains because of calcium homeostasis changes (see [160] for a critical review). Enhanced calpain activation produces augmented APP processing via BACE activation and augmented Aβ deposit [161], increases tau-mediated neuropathology [162], and disrupts the functionality of kinases such as CDK5 by pushing the cleavage of the CDK5 activator p35 [163], but also induces microgliosis, somatodendritic dystrophy, and increased mortality while the endogenous calpain inhibitor calpastatin is knocked down in animal models of AD [164]. This evidence supports the possible use of calpain inhibitors as a therapeutic treatment in AD [153][154][155].…”