Aß deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer's disease
A transgenic mouse bearing mutant transgenes linked to familial forms of Alzheimer's disease (AD) for the amyloid precursor protein and presenilin-1 (TASTPM) showed Abeta plaque deposition and age-related histological changes in associated brain pathology. The Abeta present was of multiple forms, including species with a C-terminus at position 40 or 42, as well as an N-terminus at position 1 or truncated in a pyro-3-glutamate form. Endogenous rodent Abeta was also present in the deposits. Laser capture microdissection extracts showed that multimeric forms of Abeta were present in both plaque and tissue surrounding plaques. Associated with the Abeta deposits was evidence of an inflammatory response characterised by the presence of astrocytes. Also present in close association with the deposits was phosphorylated tau and cathepsin D immunolabelling. The incidence of astrocytes and of phosphorylated tau and cathepsin D load showed that both of these potential disease markers increased in parallel to the age of the mice and with Abeta deposition. Immunohistochemical labelling of neurons in the cortex and hippocampus of TASTPM mice suggested that the areas of Abeta deposition were associated with the loss of neurons. TASTPM mice, therefore, exhibit a number of the pathological characteristics of disease progression in AD and may provide a means for assessment of novel therapeutic agents directed towards modifying or halting disease progression.
Available from: Shreaya Chakroborty
- "A nanocrystal formulation of dantrolene (Lyotropic Therapeutics, Inc., ) was administered intraperitoneally (IP, 10 mg/kg in sterile water) to AD-Tg and NonTg mice at two time points: (1) daily injections for 4 weeks starting at 2 months of age for the 3xTg-AD mice (corresponding to plaque-free stage); and (2) daily injections for 4 weeks starting at 5 months for the TASTPM (coinciding with moderate plaque formation and onset of cognitive deficits; , . Control mice were administered 0.9% saline daily. "
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ABSTRACT: Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients.
PLoS ONE 12/2012; 7(12):e52056. DOI:10.1371/journal.pone.0052056 · 3.23 Impact Factor
Available from: cnrs.fr
- "Microglial activation coincided with synaptic pathology, followed later by fibrillary tau pathology and astrogliosis . Although Howlett and colleagues found no up-regulation of microglial CD11b in TASTPM mice (double APP/PS1 transgenic), expression of Iba-1 was greatly increased  , suggesting a change in activation state. "
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ABSTRACT: Much evidence is available that inflammation contributes to the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Our review investigates how well current mouse models reflect this aspect of the pathogenesis.Transgenic models of AD have been available for several years and are the most extensively studied. Modulation of cytokine levels, activation of microglia and, to a lesser extent, activation of the complement system have been reported. Mouse models of PD and HD so far show less evidence for the involvement of inflammation.An increasing number of transgenic mouse strains is being created to model human neurodegenerative diseases. A perfect model should reflect all aspects of a disease. It is important to evaluate continuously the models for their match with the human disease and reevaluate them in light of new findings in human patients.Although none of the transgenic mouse models recapitulates all aspects of the human disorder they represent, all models have provided valuable information on basic molecular pathways. In particular, the mouse models of Alzheimer disease have also led to the development of new therapeutic strategies such as vaccination and modulation of microglial activity.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 10/2010; 1802(10-1802):889-902. DOI:10.1016/j.bbadis.2009.10.013 · 4.88 Impact Factor
Available from: dmd.aspetjournals.org
- "Animal models are important tools to study pathology and test potential treatments for CNS diseases. A transgenic mouse bearing mutant transgenes linked to familial forms of AD for the amyloid precursor protein and presenilin-1 (TASTPM) showed A plaque deposition and age-related histological changes in associated brain pathology (Howlett et al., 2008). TASTPM mice, therefore, may provide a means for assessment of novel therapeutic agents directed to modifying or halting progression of AD. "
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ABSTRACT: Therapy for central nervous system (CNS) diseases requires drugs that can cross the blood-brain barrier (BBB). BBB disruption has been reported in patients with multiple sclerosis (MS) and Alzheimer's disease (AD) and the related animal models as evidenced by increased infiltration of inflammatory cells or increased staining of Igs in the central nervous system. Although CNS penetration of therapeutic agents under pathological conditions has rarely been investigated, it is commonly assumed that BBB disruption may lead to enhanced CNS penetration and also provide a "window of opportunity" through which drugs that do not normally cross BBB are able to do so. In this article, we have compared brain penetration of eight small molecules in naive animals and experimental autoimmune encephalomyelitis (EAE) mice, streptozotocin-induced mice, and TASTPM transgenic mice. The tool compounds are lipophilic transcellular drugs [GlaxoSmithKline (GSK)-A, GSK-B, GSK-C, and naproxen], lipophilic P-glycoprotein (P-gp) substrates (amprenavir and loperamide), and hydrophilic paracellular compounds (sodium fluorescein and atenolol). Our data showed that rate and extent of CNS penetration for lipophilic transcellular drugs and P-gp substrates are similar in naive and all tested animal models. The brain penetration for paracellular drugs in EAE mice is transiently increased but similar to that in naive mice at steady state. Our data suggest that, despite reported BBB disruption, CNS penetration for small molecule therapeutic agents does not increase in MS- and AD-related animal models.
Drug metabolism and disposition: the biological fate of chemicals 08/2010; 38(8):1355-61. DOI:10.1124/dmd.110.033324 · 3.25 Impact Factor
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