Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Ribé, Elena M.; Pérez, Mar; Puig, Berta; Gich, Ignasi; Lim, Filip; Cuadrado, Mar; Sesma, Teresa; Catena, Silvia; Sanchez, B.; Nieto, Manuel; Gómez‐Ramos, Pilar; Morán, María A.; Cabodevilla, Felipe; Samaranch, Lluı́s; Ortíz, Lourdes; Pérez, Alberto; Ferrer, Isidro; Ávila, Jesús; Gómez-Isla, Teresa

doi:10.1016/j.nbd.2005.05.027

Cited by 152 publications

(125 citation statements)

References 23 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…This lowered transgene expression served to highlight the power of incorporating the London mutation, and may also reflect an effect of mutant tau, consistent with a previous report that tau accelerated APP-related pathology. 37 Despite lower levels of human APP, plaque deposition was enhanced in rTg3696AB versus Tg2576 brain. In Tg2576, previous studies observed the first formation of A␤ plaques between 7 and 10 months of age.…”

Section: Discussionmentioning

confidence: 99%

“…41 Other groups observed an increase in both A␤ deposition and NFT pathology in Tg2576 crossed with mice harboring three mutations in tau (VLW; G272V, P301L and R406W). 37 In this model, an increase in tau phosphorylation was hypothesized to reciprocate a link between the two pathological cascades. 42 Unfortunately, a clear demonstration of the molecular connection between A␤ plaques and NFTs remains enigmatic.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Paulson

Ramsden

Forster

et al. 2008

The American Journal of Pathology

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Paulson

Ramsden

Forster

et al. 2008

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…An association between Aβ and hyperphosphorylated tau has been shown (Ribe et al, 2005;Oddo et al, 2003). Soluble Aβ can induce inactivation of phosphatases (Vogelsberg-Ragaglia et al, 2001) and activation of tau kinases (Hoshi et al, 2003;Otth et al, 2002), and promoting tau phosphorylation (Hoshi et al, 2003;Otth et al, 2002;Zheng et al, 2002) and the direct interaction between tau and Aβ induces tau aggregation and hyperphosphorylation (Rank et al, 2002).…”

Section: Interplay Between Dyrk1a Aβ and Taumentioning

confidence: 99%

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

García-Cerro

Rueda

Vidal

et al. 2017

Neurobiology of Disease

View full text Add to dashboard Cite

The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including DYRK1A (dualspecificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the DYRK1A gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of APP and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.

show abstract

“…We used the Morris water maze (MWM) test to evaluate the working and reference memory function in response to treatment with 4-PBA in Tg2576 mice, as previously described (Ribé et al, 2005). Groups of female Tg2576 mice treated with 4-PBA (n ¼ 8), or vehicle (n ¼ 8) and nontransgenic littermates (n ¼ 10) underwent spatial reference learning and memory testing in the MWM test at 16 months of age.…”

Section: Morris Water Maze Testmentioning

confidence: 99%

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Ricobaraza

Cuadrado‐Tejedor

Pérez-Mediavilla

et al. 2009

Neuropsychopharmacol

371

265

View full text Add to dashboard Cite

Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering b-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3b (GSK3b). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

show abstract

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice

Cited by 152 publications

References 23 publications

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

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

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Contact Info

Product

Resources

About