Amyloid Plaque and Neurofibrillary Tangle Pathology in a Regulatable Mouse Model of Alzheimer's Disease

Abstract

Transgenic mouse models that independently express mutations in amyloid precursor protein (APP) and tau have proven useful for the study of the neurological consequences of amyloid-␤ (A␤) plaque and neurofibrillary tangle pathologies. Studies using these mice have yielded essential discoveries with regard to specific aspects of neuronal dysfunction and degeneration that characterize the brain during Alzheimer's disease (AD) and other age-dependent tauopathies. Most recent transgenic studies have focused on the creation of regulatable models that allow the temporal control of transgene expression. To study a more complete model of AD pathology, we designed a new regulatable transgenic mouse that harbors both APP and tau transgenes. Here, we present a novel transgenic mouse model, rTg3696AB, which expresses human APP NLI and tau P301L driven by the CaMKII promoter system. Subsequent generation of A␤ and 4R0N tau in the brain resulted in the development of three neuropathological features of AD: A␤ plaques, neurofibrillary tangles, and neurodegeneration. Importantly, transgene expression in these mice is regulatable, permitting temporal control of gene expression and the investigation of transgene suppression. The diagnosis of Alzheimer's disease (AD) is confirmed after postmortem examination and is dependent on the identification of senile plaques and neurofibrillary tangles (NFTs). In addition to neuronal loss, these extracellular deposits of ␤-amyloid (A␤) peptide and intraneuronal accumulations of hyperphosphorylated tau represent the histological hallmarks of this devastating neurological disorder.1 For almost a century, AD researchers believed that accumulation of insoluble A␤ and tau species represented a purely detrimental event in the brain. However, recent studies have questioned this assumption and confirmed that the true pathological relevance of these neuronal lesions is still not completely understood.Experiments using transgenic mice have been particularly valuable for independently studying the progression of plaque and NFT pathologies. Studies using mice that express amyloid precursor protein (APP) have provided significant insights regarding the contribution of A␤ plaques to brain dysfunction. In APP transgenic mice, plaques are associated with dendritic spine loss, neuritic dystrophy, neuronal death, and abnormal axonal morphology, 2-8 which lead to a subsequent disruption of synaptic integration. 9 Although it is believed that A␤ plaques play a fundamental role in the pathology of AD, their precise contribution to neurodegeneration is unclear. Interpreting the significance of amyloid plaques has been complicated by advances in the study of A␤, their primary component. It is now known that A␤ exists in many distinctly different forms. These include monomers of A␤, low-and high-molecular weight soluble A␤ oligomers, A␤-derived diffusible ligands, amyloid pores, protofibrils, and fibrils. 10 -17 In turn, these specific A␤ species have been shown to exert a myriad of neurotoxic and dysfunctional ef...

Tau-Induced Defects in Synaptic Plasticity, Learning, and Memory Are Reversible in Transgenic Mice after Switching Off the Toxic Tau Mutant

“…Several transgenic mouse models have been generated to study these aggregates (Ballatore et al, 2007; for review, see Götz and Ittner, 2008;Paulson et al, 2008;Small and Duff, 2008;Morrissette et al, 2009). Mouse models developing A␤ aggregates are based on mutations in APP or secretases but do not cause Tau aggregation.…”

Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice

“…Double transgenic mice expressing mutants APP and tau proteins develop an enhanced tau pathology (Bolmont et al, 2007;Hurtado et al, 2010;Lewis et al, 2001;Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008). The enhancement of tauopathy by Aß accumulation in APP/tau models has been described in some models as slow, developing with aging, and relatively modest (Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008). The mechanisms of worsened tau pathology in these APP/tau models are however not well understood, and potential additional misprocessing of tau in these APP/tau models compared to tau in FTD tau models has not been clarified.…”

“…Injection of Aß (Gotz et al, 2001) or of Aβ-containing brain extract from APP mice (Bolmont et al, 2007) was reported to increase NFT formation in mutant P301L tau mice. Double transgenic mice expressing mutants APP and tau proteins develop an enhanced tau pathology (Bolmont et al, 2007;Hurtado et al, 2010;Lewis et al, 2001;Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008). The enhancement of tauopathy by Aß accumulation in APP/tau models has been described in some models as slow, developing with aging, and relatively modest (Paulson et al, 2008;Perez et al, 2005;Seino et al, 2010;Terwel et al, 2008).…”

Application of APP/PS1 Transgenic Mouse Model for Alzheimer’s Disease

“…They are established on the basis of genetics, mainly involves amyloid precursor protein(APP) gene on chromosome 21, presenilin1 (PS1) gene on chromosome 14, presenilin 2 (PS2) gene on chromosome 1, Tau protein gene on chromosome 17 and Apolipoprotein E (ApoE) gene on chromosome 19 [14]. By transgenesis, the course of AD can be simulated steadily at molecular level.…”