Mechanisms of Neural and Behavioral Dysfunction in Alzheimer’s Disease (original) (raw)
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Frontiers in genetics, 2014
The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition),...
Frontiers in behavioral neuroscience, 2014
Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg(+/-)) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed S...
A Longitudinal Study of Behavioral Deficits in an AβPP Transgenic Mouse Model of Alzheimer's Disease
Journal of Alzheimer's Disease, 2011
Elucidating the age-dependent alterations in transgenic (Tg) mice overexpressing amyloid-β protein precursor (AβPP) is important for understanding the pathogenesis of Alzheimer's disease (AD) and designing experimental therapies. Cross-studies have previously characterized some time-dependent behavioral and pathological alterations in AβPP Tg mice, however, a more comprehensive longitudinal study is needed to fully examine the progressive nature of behavioral deficits in these mice. In order to better understand the age-and gender-dependent progression of behavioral alterations, we performed a longitudinal study wherein Tg mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the neuron specific murine (m)Thy-1 promoter (mThy1-hAβPP751) were behaviorally analyzed at 3 months and then re-tested at 6 and 9 months of age. The results show that there was an age-associated impairment in learning in the water maze task and habituation in the hole-board task. Motor coordination of the mThy1-hAβPP751 Tg mice was well-preserved throughout the investigated life span however, gender-specific deficits were observed in spontaneous activity and thigmotaxis. Neuropathologically, mThy1-hAβPP751 Tg mice displayed a progressive increase in the number of Aβ plaques and mean plaque size in the cortex and hippocampus from 3 to 6 and from 6 to 9 months of age. Taken together, these results indicate that the mThy1-hAβPP751 Tg mice model AD from the early onset of the disease through to later stages, allowing them to be utilized at numerous points during the timeline for drug test designs.
The Journal of Neuroscience, 2011
The unique vulnerability of the olfactory system to Alzheimer's disease (AD) provides a quintessential translational tool for understanding mechanisms of synaptic dysfunction and pathological progression in the disease. Using the Tg2576 mouse model of -amyloidosis, we show that aberrant, hyperactive olfactory network activity begins early in life, before detectable behavioral impairments or comparable hippocampal dysfunction and at a time when amyloid- (A) deposition is restricted to the olfactory bulb (OB). Hyperactive odor-evoked activity in the piriform cortex (PCX) and increased OB-PCX functional connectivity emerged at a time coinciding with olfactory behavior impairments. This hyperactive activity persisted until later in life when the network converted to a hyporesponsive state. This conversion was A-dependent, because liver-X receptor agonist treatment to promote A degradation rescued the hyporesponsive state and olfactory behavior. These data lend evidence to a novel working model of olfactory dysfunction in AD and, complimentary to other recent works, suggest that disease-relevant network dysfunction is highly dynamic and region specific, yet with lasting effects on cognition and behavior.
Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease
Proceedings of The National Academy of Sciences, 2006
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of -amyloid (A)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the A42͞A40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until Ϸ18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.
bioRxiv (Cold Spring Harbor Laboratory), 2023
Alzheimer's disease (AD) progresses with memory loss and neuropsychiatric symptoms associated with cell specific vulnerability in memory-and emotion-related neural circuits. Neuropathological and synaptic changes are key factors influencing the clinical progression to dementia, but how they cooperate to cause memory and emotional disturbances is largely unknown. Here, we employed pathological, behavioral, expansion microscopy, electrophysiology and transcriptomic approaches to evaluate the effects of amyloid-β (Aβ) and tau on neuropathological progression, synaptic function, and memory and emotional symptoms in amyloid precursor protein (APP), Tau and double novel APP/Tau transgenic mice expressing the mutant human amyloid precursor protein (APPSw,Ind) and/or microtubuleassociated protein tau (MAPT) in excitatory neurons. APP/Tau mice of both sexes show spatial learning and memory deficits associated with synaptic tau accumulation and reduced synaptic proteins and neurotransmission in the hippocampus. By contrast, male and female APP/Tau mice exhibit innate anxious behavior and impaired fear memory extinction linked to Aβ pathology and with absence of synaptic tau in the basolateral amygdala (BLA). Intriguingly, APP/Tau mice show NMDA-dependent long-term potentiation (LTP) deficits in the hippocampus but not in the amygdala. Bulk RNA sequencing reveals region-specific but also common transcriptional changes in response to Aβ/tau pathology, including downregulation of synapse transmission and ion channel activity genes. Importantly, we detected 65 orthologs of human AD risk genes identified in GWAS (
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
Recent rodent models for Alzheimer’s disease: clinical implications and basic research
Journal of Neural Transmission, 2012
Alzheimer's disease (AD) is the most common origin of dementia in the elderly. Although the cause of AD remains unknown, several factors have been identified that appear to play a critical role in the development of this debilitating disorder. In particular, amyloid precursor protein (APP), tau hyperphosphorylation, and the secretase enzymes, have become the focal point of recent research. Over the last two decades, several transgenic and nontransgenic animal models have been developed to elucidate the mechanistic aspects of AD and to validate potential therapeutic targets. Transgenic rodent models overexpressing human b-amyloid precursor protein (b-APP) and mutant forms of tau have become precious tools to study and understand the pathogenesis of AD at the molecular, cellular and behavioural levels, and to test new therapeutic agents. Nevertheless, none of the transgenic models of AD recapitulate fully all of the pathological features of the disease. Octodon degu, a South American rodent has been recently found to spontaneously develop neuropathological signs of AD in old age. This review aims to address the limitations and clinical relevance of transgenic rodent models in AD, and to highlight the potential for O. degu as a natural model for the study of AD neuropathology.