Transgenic Mice as a Model of Pre-Clinical Alzheimers Disease (original) (raw)
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Molecular and cellular pathophysiology of preclinical Alzheimer's disease
Although the two pathological hallmarks of Alzheimer's disease (AD), senile plaques composed of amyloid-(A) peptides and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau, have been studied extensively in postmortem AD and relevant animal and cellular models, the pathogenesis of AD remains unknown, particularly in the early stages of the disease where therapies presumably would be most effective. We and others have demonstrated that A plaques and NFTs are present in varying degrees before the onset and throughout the progression of dementia. In this regard, aged people with no cognitive impairment (NCI), mild cognitive impairment (MCI, a presumed prodromal AD transitional state, and AD all present at autopsy with varying levels of pathological hallmarks. Cognitive decline, a requisite for the clinical diagnosis of dementia associated with AD, generally correlates better with NFTs than A plaques. However, correlations are even higher between cognitive decline and synaptic loss. In this review, we illustrate relevant clinical pathological research in preclinical AD and throughout the progression of dementia in several areas including A and tau pathobiology, single population expression profiling of vulnerable hippocampal and basal forebrain neurons, neuroplasticity, neuroimaging, cerebrospinal fluid (CSF) biomarker studies and their correlation with antemortem cognitive endpoints. In each of these areas, we provide evidence for the importance of studying the pathological hallmarks of AD not in isolation, but rather in conjunction with other molecular, cellular, and imaging markers to provide a more systematic and comprehensive assessment of the multiple changes that occur during the transition from NCI to MCI to frank AD.
Early molecular changes in Alzheimer disease: can we catch the disease in its presymptomatic phase?
2014
Alzheimer Disease (AD) is the most common form of dementia and characterized by deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, atrophy and progressive neurodegeneration. While the familial, early onset form of AD is known to be caused by specific mutations in genes encoding presenilin 1, presenilin 2 or Aß protein precursor, the underlying mechanisms leading to the development of sporadic AD are still not known. The major risk factors are, however, aging and APO-ε4. Here we review the latest evidence for the involvement of malfunctioning insulin signaling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism and synaptic dysfunction in early stages of AD. We focus on whether the changes in these processes precede or succeed the earliest symptoms in AD patients, i.e. minimal cognitive impairment. Since changes in Aß processing are probably a key event in AD we also highlight the relationship of the above mentioned processes with the formation, secretion, aggregation and toxicity of Aβ. Based on our literature findings we propose a model in which insulin dysfunction, pathological cerebrovascular changes, dysfunction of mitochondria-associated membranes and/ or synaptic changes are likely to interact with each other, thereby initiating and facilitating the development of AD pathology by accelerating the production and deposition of Aß. Increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism and synaptic loss follow these events, but still occur very early in AD.
Defining the earliest pathological changes of Alzheimer's disease
Current Alzheimer research, 2016
The prospects for effectively treating well-established dementia, such as Alzheimer's disease (AD), are slim, due to the destruction of key brain pathways that underlie higher cognitive function. There has been a substantial shift in the field towards detecting conditions such as AD in their earliest stages, which would allow preventative or therapeutic approaches to substantially reduce risk and/or slow the progression of disease. AD is characterized by hallmark pathological changes such as extracellular Aβ plaques and intracellular neurofibrillary pathology, which selectively affect specific subclasses of neurons and brain circuits. Current evidence indicates that Aβ plaques begin to form many years before overt dementia, a gradual and progressive pathology which offers a potential target for early intervention. Early Aβ changes in the brain result in localized damage to dendrites, axonal processes and synapses, to which excitatory synapses and the processes of projection neur...
Neuron, 2005
many critical aspects of AD neuropathology: (1) amyloid plaques and neurofibrillary pathology develop in James L. McGaugh, and Frank M. LaFerla* a hierarchical manner in AD-relevant brain regions, Department of Neurobiology and Behavior and mainly the hippocampus, cortex, and amygdala; (2) Center for the Neurobiology of Learning and Memory plaque pathology precedes tangle formation, and plaques University of California, Irvine consist of the longer, more amyloidogenic Aβ 42 ; (3) the Irvine, California 92697 pattern of conformational and phosphorylation changes that the tau protein undergoes parallels the sequence in the human AD brain; (4) the 3xTg-AD mice show se-Summary lective loss of nicotinic α7 receptors in the hippocampus and cortex (Oddo et al., 2003, 2005). These mice Progressive memory loss and cognitive dysfunction also develop dysfunction in synaptic plasticity, includare the hallmark clinical features of Alzheimer's dising deficits in LTP and paired-pulse facilitation, in conease (AD). Identifying the molecular triggers for the junction with the early, intraneuronal accumulation of onset of AD-related cognitive decline presently re-Aβ (Oddo et al., 2003). quires the use of suitable animal models, such as the It is presently unclear how the hallmark features of 3xTg-AD mice, which develop both amyloid and tan-AD neuropathology, plaques and tangles, relate to the gle pathology. Here, we characterize the onset of emergence of cognitive impairments. It is well establearning and memory deficits in this model. We report lished that the number of plaques does not correlate that 2-month-old, prepathologic mice are cognitively with cognitive performance in AD patients (Arriagada et unimpaired. The earliest cognitive impairment manial., 1992; Samuel et al., 1994). In contrast, it appears fests at 4 months as a deficit in long-term retention that total Aβ load is a better measure (Cummings and and correlates with the accumulation of intraneuronal Cotman, 1995). Although the number of tangles is a A in the hippocampus and amygdala. Plaque or tanbetter predictive measure of overall cognitive function gle pathology is not apparent at this age, suggesting in humans with a clinical AD diagnosis (McKee et al., that they contribute to cognitive dysfunction at later 1991), tangles still do not present a reliable biomarker time points. Clearance of the intraneuronal A patholfor the onset of early cognitive changes. Synaptic loss ogy by immunotherapy rescues the early cognitive appears to be the best correlate of the cognitive dysdeficits on a hippocampal-dependent task. Reemerfunction in AD patients (Terry et al., 1991), although the gence of the A pathology again leads to cognitive trigger underlying the synaptic pathology is not yet redeficits. This study strongly implicates intraneuronal solved. The human studies are corroborated by data A in the onset of cognitive dysfunction. from various transgenic mouse models of AD in which it appears that cognitive impairments emerge prior to Introduction any overt neuropathology and correlate poorly with plaque number (Mucke et al., 1994; Hsiao, 1995; Moe-Alzheimer's disease (AD) is a progressive neurodegenchars et al., 1999; Dodart et al., 2002). The sum of these erative disorder and the most common cause of destudies, however, does not rule out an early, pathogenic mentia worldwide. Episodic memory, which is defined form of amyloid as the trigger for the onset of cognitive as the ability to recall past experiences, is disrupted in dysfunction in both humans and transgenic mice. AD and typically appears to be the first cognitive do-In this study, we sought to define the molecular trigmain that is impacted in AD patients (Welsh et al., 1992; ger for the onset of cognitive decline in a transgenic Artero et al., 2003). As the disease progresses, other model of AD. We examined 3xTg-AD mice for learning cognitive deficits manifest, particularly in attention and and memory deficits in spatial reference and contextual executive functions, semantic memory, language, and learning tasks, which involve the hippocampus and spatial orientation (Perry and Hodges, 1999; Lambon also the amygdala, respectively (Sutherland and Mc-Ralph et al., 2003). Criteria for the clinical diagnosis of Donald, 1990; Davis, 1992; Nakazawa et al., 2004). Both AD are achieved once cognitive deficits become secross-sectional and longitudinal analyses were pervere enough to disrupt normal social and occupaformed, allowing us to track the long-term performance tional function. of each mouse and compare it to age-and sex-The molecular, cellular, and pathological changes matched naive mice at each time point. We report that that trigger the onset of cognitive decline in the AD brain prepathologic 3xTg-AD mice perform comparably to are presently unknown and are an intractable problem age-matched nontransgenic (NonTg) mice. We find that to address in humans until brain imaging achieves the initial cognitive impairments manifest as a retention higher spatial and temporal resolution. Hence, animal deficit, as the 3xTg-AD mice effectively learn both tasks models remain invaluable tools for identifying the mobut fail to retain essential information from day to day. lecular markers that trigger the onset of AD-related These findings parallel the changes reported in humans cognitive decline. Toward this end, our lab generated with mild cognitive impairment (MCI), which involves a a triple-transgenic model of AD (3xTg-AD) that mimics deterioration in episodic memory with the maintenance of other cognitive processes (Grundman et al., 2004). We further show that the retention deficits correlate
Background: Alzheimer’s disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing. Results: The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy (1H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. Conclusions: Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.
Altered gene expression and neuropathology in Alzheimer's disease
Neurobiology of Aging, 2006
In their review article published in this issue of Neurobiology of Aging, Reddy and McWeeney provide an overview on the neuropathology of Alzheimer's disease (AD), genes related to AD, transgenic animal models of AD, and results from studies which have focused on alterations in gene expression in AD, performed both on postmortem brains from patients with AD and controls as well as on transgenic mouse models of this disease. Their major conclusion is that findings from studies carried out to date on alterations in gene expression in AD are still limited in terms of their utility in treating AD patients and in developing early methods of detection. We generally agree with most of the ideas and trajectories of Reddy and McWeeney . However, we would like to draw attention to the following issues.
Pathobiology of Aging & Age-related Diseases, 2016
Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Ab and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Ab and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1) cerebrospinal fluid (CSF) AD biomarker changes with reduced Ab and increased phospho-tau/tau; 2) structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG), and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3) cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Ab deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines and standards for models of AD and other neurodegenerative disorders.
Behavioural Brain Research, 2009
Current transgenic mouse models of Alzheimer disease constitute a relevant tool to examine the relationships between neuropathological lesions, neurodegeneration and clinical syndromes. Nevertheless, addressing the relation between A deposition and cognition deterioration requires careful adjustment for age to decipher underlying mechanisms of impairments and identify potential therapeutic targets. In the present work we have carried out a detailed behavioral analysis of the APP 751SL transgenic mouse model testing 6 age-points (from 2 to 19-20 months) and estimating in parallel the cerebral A deposition. The immunohistochemistry study indicated a fast progression of A 17-24 staining in several brain structures that reached for most of them, a maximal level at 7-8 months of age. Behavioral experiments showed that APP 751SL mice displayed alterations in some general functions (muscular strength, motor activity) whereas other functions are preserved (anxiety, exploration). Acquisition and extinction of an appetitive operant conditioning were used to assess early learning deficits. Hippocampal but not dorsolateral striatal lesion was shown to delay extinction. Although some learning deficits were detected at 5-6 months in the acquisition of the operant conditioning task, more robust impairments in extinction were observed in 7-8-month-old mice. Indeed, spatial memory deficit was associated to a selective hippocampal CA1 impairment of learning-induced Zif268 activation. Because this mouse model displayed gradual memory deficits it gives the opportunity to investigate the temporal progression of molecular and cellular mechanisms that induce cognitive decline. (J. Micheau). genes involved in AD have been created . The target proteins are, for example, the amyloid precursor protein (APP), the presinilins (PS1 and PS2), tau, and their normal wild-type forms, or genes representing a risk factor for developing the disease, such as apolipoprotein E (Apo E4). Transgenic mice for mutant human APP show a time-dependant increase in extracellular A and develop certain neuropathological and even behavioral changes reminiscent of AD . These engineered mouse models have enabled a controlled temporal dissection of the pathogenic processes and exploration of the suitability of therapeutic interventions for symptomatic or disease-modifying treatment . Recent studies have reported that in transgenic mouse model of AD, molecular, morphological, functional and behavioral deficits can be measured for extended periods preceding the first evidence of plaque formation , suggesting that soluble A induced earliest cognitive impairments.
Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches
ACS Omega
A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various preclinical models are available for several diseases, clinical models for Alzheimer's disease (AD) remain underdeveloped and inaccurate. The pathophysiology of AD mainly includes the presence of amyloid plaques and neurofibrillary tangles (NFT). Furthermore, neuroinflammation and free radical generation also contribute to AD. Currently, there is a wide gap in scientific approaches to preventing AD progression. Most of the available drugs are limited to symptomatic relief and improve deteriorating cognitive functions. To mimic the pathogenesis of human AD, animal models like 3XTg-AD and 5XFAD are the primarily used mice models in AD therapeutics. Animal models for AD include intracerebroventricular-streptozotocin (ICV-STZ), amyloid beta-induced, colchicine-induced, etc., focusing on parameters such as cognitive decline and dementia. Unfortunately, the translational rate of the potential drug candidates in clinical trials is poor due to limitations in imitating human AD pathology in animal models. Therefore, the available preclinical models possess a gap in AD modeling. This paper presents an outline that critically assesses the applicability and limitations of the current approaches in disease modeling for AD. Also, we attempted to provide key suggestions for the best-fit model to evaluate potential therapies, which might improve therapy translation from preclinical studies to patients with AD.