Deficits in odor-guided behaviors in the transgenic 3xTg-AD female mouse model of Alzheimer׳s disease

Coronas‐Samano, Guillermo; Portillo, Wendy; Campos, Vicente; Medina-Aguirre, G.I.; Paredes, Raúl G.; Dı́az-Cintra, Sofı́a

doi:10.1016/j.brainres.2014.05.013

Cited by 18 publications

(13 citation statements)

References 41 publications

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“…Amyl acetate (AA) is an often used banana-like food odorant. Last, we used social odor (SO), as prior work had shown this stimulus to evoke longer exploration times (Coronas-Sámano et al, 2014), thereby enhancing the sensitivity of the test. There was an overall effect on exploration time across the odors [ F (2.95, 62.02) = 11.68, P < 0.001; one-way RM ANOVA, N = 22, Figure 2] in the Fus1 KO mice.…”

Section: Resultsmentioning

confidence: 99%

“…Ranging from Warner's smell identification studies testing patients at different stages of disease (Warner et al, 1986), to the olfactory experiments testing transgenic animal models for AD (Coronas-Sámano et al, 2014; Roddick et al, 2016), it has been proposed that there is a decrement in the ability to identify, discriminate and remember a wide variety of odorants. Interestingly, while Fus1 KO animals showed somewhat poor long-term odor memory compared to their WT counterparts, short-term memory was not clearly adversely affected.…”

Section: Discussionmentioning

confidence: 99%

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Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

Coronas‐Samano

Baker

Tan

et al. 2016

Front. Aging Neurosci.

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Insufficient advances in the development of effective therapeutic treatments of sporadic Alzheimer's Disease (sAD) to date are largely due to the lack of sAD-relevant animal models. While the vast majority of models do recapitulate AD's hallmarks of plaques and tangles by virtue of tau and/or beta amyloid overexpression, these models do not reflect the fact that in sAD (unlike familial AD) these genes are not risk factors per se and that other mechanisms like oxidative stress, metabolic dysregulation and inflammation play key roles in AD etiology. Here we characterize and propose the Fus1 KO mice that lack a mitochondrial protein Fus1/Tusc2 as a new sAD model. To establish sAD relevance, we assessed sAD related deficits in Fus1 KO and WT adult mice of 4–5 months old, the equivalent human age when the earliest cognitive and olfactory sAD symptoms arise. Fus1 KO mice showed oxidative stress (increased levels of ROS, decreased levels of PRDX1), disruption of metabolic homeostasis (decreased levels of ACC2, increased phosphorylation of AMPK), autophagy (decreased levels of LC3-II), PKC (decreased levels of RACK1) and calcium signaling (decreased levels of Calb2) in the olfactory bulb and/or hippocampus. Mice were behaviorally tested using objective and accurate video tracking (Noldus), in which Fus1 KO mice showed clear deficits in olfactory memory (decreased habituation/cross-habituation in the short and long term), olfactory guided navigation memory (inability to reduce their latency to find the hidden cookie), spatial memory (learning impairments on finding the platform in the Morris water maze) and showed more sleep time during the diurnal cycle. Fus1 KO mice did not show clear deficits in olfactory perception (cross-habituation), association memory (passive avoidance) or in species-typical behavior (nest building) and no increased anxiety (open field, light-dark box) or depression/anhedonia (sucrose preference) at this relatively young age. These neurobehavioral deficits of the Fus1 KO mice at this relatively young age are highly relevant to sAD, making them suitable for effective research on pharmacological targets in the context of early intervention of sAD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

Coronas‐Samano

Baker

Tan

et al. 2016

Front. Aging Neurosci.

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“…Interestingly, the loss of the sense of smell is one of the earliest signs of PD, a symptom reported years before the onset of motor symptoms [ 47 ]. Additionally, olfactory deficits are being investigated as a diagnostic approach to detect and discriminate between depression and Alzheimer's disease (AD) in the elderly [ 44 ], given that olfactory deficits are also an early symptom of AD [ 48 ]. Together, these findings corroborate with PQ and MB treatments affecting neuronal pathways and point to the importance of carbonylation in the modification of neuronal activity and function.…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteomic Analysis of Carbonylated Proteins from the Striatum and Cortex of Pesticide-Treated Mice

Coughlan

Walker

Lohr

et al. 2015

Parkinson's Disease

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Epidemiological studies indicate exposures to the herbicide paraquat (PQ) and fungicide maneb (MB) are associated with increased risk of Parkinson's disease (PD). Oxidative stress appears to be a premier mechanism that underlies damage to the nigrostriatal dopamine system in PD and pesticide exposure. Enhanced oxidative stress leads to lipid peroxidation and production of reactive aldehydes; therefore, we conducted proteomic analyses to identify carbonylated proteins in the striatum and cortex of pesticide-treated mice in order to elucidate possible mechanisms of toxicity. Male C57BL/6J mice were treated biweekly for 6 weeks with saline, PQ (10 mg/kg), MB (30 mg/kg), or the combination of PQ and MB (PQMB). Treatments resulted in significant behavioral alterations in all treated mice and depleted striatal dopamine in PQMB mice. Distinct differences in 4-hydroxynonenal-modified proteins were observed in the striatum and cortex. Proteomic analyses identified carbonylated proteins and peptides from the cortex and striatum, and pathway analyses revealed significant enrichment in a variety of KEGG pathways. Further analysis showed enrichment in proteins of the actin cytoskeleton in treated samples, but not in saline controls. These data indicate that treatment-related effects on cytoskeletal proteins could alter proper synaptic function, thereby resulting in impaired neuronal function and even neurodegeneration.

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“…Neurogenesis declines during normal aging (Lazarov et al ., ), and in amyloid precursor protein (APP)‐mutant mice (Haughey et al ., ), which also exhibit impaired olfaction (Guerin et al ., ). It was recently reported that 3xTgAD mice exhibit a deficit in a sexual olfactory preference test (Coronas‐Sámano et al ., ), but the underlying cellular and molecular mechanisms are unknown.…”

Section: Introductionmentioning

confidence: 99%

DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease

et al. 2016

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SummaryAlzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase‐β (Polβ) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD. We interrogated OB histopathology and olfactory function in wild‐type and 3xTgAD mice with normal or reduced Polβ levels. Compared to wild‐type control mice, Polβ heterozygous (Polβ+/−), and 3xTgAD mice, 3xTgAD/Polβ+/− mice exhibited impaired performance in a buried food test of olfaction. Polβ deficiency did not affect the proliferation of OB neural progenitor cells in the subventricular zone. However, numbers of newly generated neurons were reduced by approximately 25% in Polβ+/− and 3xTgAD mice, and by over 60% in the 3xTgAD/Polβ+/− mice compared to wild‐type control mice. Analyses of DNA damage and apoptosis revealed significantly greater degeneration of OB neurons in 3xTgAD/Polβ+/− mice compared to 3xTgAD mice. Levels of amyloid β‐peptide (Aβ) accumulation in the OB were similar in 3xTgAD and 3xTgAD/Polβ+/− mice, and cultured Polβ‐deficient neurons exhibited increased vulnerability to Aβ‐induced death. Olfactory deficit is an early sign in human AD, but the mechanism is not yet understood. Our findings in a new AD mouse model demonstrate that diminution of BER can endanger OB neurons, and suggest a mechanism underlying early olfactory impairment in AD.

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Deficits in odor-guided behaviors in the transgenic 3xTg-AD female mouse model of Alzheimer׳s disease

Cited by 18 publications

References 41 publications

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

Comparative Proteomic Analysis of Carbonylated Proteins from the Striatum and Cortex of Pesticide-Treated Mice

DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease

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