5xFAD Mouse

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Minho Moon - One of the best experts on this subject based on the ideXlab platform.

  • nurr1 nr4a2 regulates alzheimer s disease related pathogenesis and cognitive function in the 5xFAD Mouse model
    Aging Cell, 2019
    Co-Authors: Minho Moon, Eun Sun Jung, Seong Gak Jeon, Moon Yong Cha, Yongwoo Jang, Woori Kim, Claudia Lopes
    Abstract:

    The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)-related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron-specific manner in AD-related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1's expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD Mouse model and postmortem human AD subjects. In addition, we performed both gain-of-function and loss-of-function studies of Nurr1 and its pharmacological activation in 5xFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5xFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD-related pathophysiology and identify Nurr1 as a novel AD therapeutic target.

  • correlation between orphan nuclear receptor nurr1 expression and amyloid deposition in 5xFAD mice an animal model of alzheimer s disease
    Journal of Neurochemistry, 2015
    Co-Authors: Minho Moon, Inhye Jeong, Pierre Leblanc
    Abstract:

    The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. Since Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer’s disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aβ accumulation, i.e., the subiculum and the frontal cortex, in the 5xFAD Mouse and that Nurr1 is highly co-expressed with Aβ at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5xFAD Mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression.

  • correlation between orphan nuclear receptor nurr1 expression and amyloid deposition in 5xFAD mice an animal model of alzheimer s disease
    Journal of Neurochemistry, 2015
    Co-Authors: Minho Moon, Pierre Leblanc, Inhye Jeong, Chunhyung Kim, Jihong Kim, Paula K J Lee, Kwangsoo Kim
    Abstract:

    The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. As Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer's disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aβ accumulation, that is, the subiculum and the frontal cortex, in the 5xFAD Mouse and that Nurr1 is highly co-expressed with Aβ at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5xFAD Mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression. Using our newly developed Nurr1-selective antibody, we show that Nurr1 protein is prominently expressed in brain areas accumulating amyloid-beta (Aβ) in the transgenic Mouse model of Alzheimer's disease (AD) and that Nurr1 is highly co-expressed with Aβ at early stages (upper panel). Furthermore, in the AD brain the number of Nurr1-expressing cells significantly declines in an age-dependent manner concomitant with increased Aβ accumulation (lower diagram) highlighting a possible Nurr1 involvement in AD pathology.

  • inhibition of glutaminyl cyclase ameliorates amyloid pathology in an animal model of alzheimer s disease via the modulation of γ secretase activity
    Journal of Alzheimer's Disease, 2014
    Co-Authors: Hyundong Song, Minho Moon, Yu Jin Chang, Sarah Kyua Park, Phuong Thao Tran, Van Hai Hoang, Inhee Mookjung
    Abstract:

    Alzheimer's disease is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, senile plaques, and neuron loss. Amyloid- peptides (A) are generated from amyloid- precursor protein by consecutive catalysis by - and -secretases. Diversely modified forms of A have been discovered, including pyroglutamate A (N3pE-42 A). N3pE-42 A has received considerable attention as one of the major constituents of the senile plaques of AD brains due to its higher aggregation velocity, stability, and hydrophobicity compared to the full-length A. A previous study suggested that N3pE-42 A formation is catalyzed by glutaminyl cyclase (QC) following limited proteolysis of A at the N-terminus. Here, we reveal that decreasing the QC activity via application of a QC inhibitor modulates -secretase activity, resulting in diminished plaque formation as well as reduced N3pE-42 A aggregates in the subiculum of the 5xFAD Mouse model of AD. This study suggests a possible novel mechanism by which QC regulates A formation, namely modulation of -secretase activity.

  • quantitative proteomic analysis of the hippocampus in the 5xFAD Mouse model at early stages of alzheimer s disease pathology
    Journal of Alzheimer's Disease, 2013
    Co-Authors: Ingie Hong, Taewook Kang, Yong Cheol Yoo, Royun Park, Junuk Lee, Sukwon Lee, Jeongyeon Kim, Boemjong Song, Seyoung Kim, Minho Moon
    Abstract:

    Alzheimer's disease (AD) is characterized by progressive memory loss accompanied by synaptic and neuronal degeneration. Although research has shown that substantial neurodegeneration occurs even during the early stages of AD, the detailed mechanisms of AD pathogenesis are largely unknown because of difficulties in diagnosis and limitations of the analytical methods. The 5xFAD Mouse model harbors five early-onset familial AD (FAD) mutations and displays substantial amyloid plaques and neurodegeneration. Here, we use quantitative mass spectrometry to identify proteome-wide changes in the 5xFAD Mouse hippocampus during the early stages of AD pathology. A subset of the results was validated with immunoblotting. We found that the 5xFAD mice display higher expression of ApoE, ApoJ (clusterin), and nicastrin, three important proteins in AD that are known to participate in amyloid-β processing and clearance, as well as the neurological damage/glial marker protein GFAP and other proteins. A large subset of the proteins that were up- or downregulated in 5xFAD brains have been implicated in neurological disorders and cardiovascular disease, suggesting an association between cardiovascular disease and AD. Common upstream regulator analysis of upregulated proteins suggested that the XBP1, NRF2, and p53 transcriptional pathways were activated, as was IGF-1R signaling. Protein interactome analysis revealed an interconnected network of regulated proteins, with two major sub-networks centered on AβPP processing membrane complexes and mitochondrial proteins. Together with a recent study on the transcriptome of 5xFAD mice, our study allows a comprehensive understanding of the molecular events occurring in 5xFAD mice during the early stages of AD pathology.

Richard E. Brown - One of the best experts on this subject based on the ideXlab platform.

  • intact olfactory memory in the 5xFAD Mouse model of alzheimer s disease from 3 to 15 months of age
    Behavioural Brain Research, 2020
    Co-Authors: Timothy P Oleary, Kurt R Stover, H M Mantolino, Sultan Darvesh, Richard E. Brown
    Abstract:

    Alzheimer's disease (AD) is an age-related neurodegenerative disorder that causes profound cognitive dysfunction. Deficits in olfactory memory occur in early stages of AD and may be useful in AD diagnosis. The 5xFAD Mouse is a commonly used model of AD, as it develops neuropathology, cognitive and sensori-motor dysfunctions similar to those seen in AD. However, olfactory memory dysfunction has not been studied adequately or in detail in 5xFAD mice. Furthermore, despite sex differences in AD prevalence and symptom presentation, few studies using 5xFAD mice have examined sex differences in learning and memory. Therefore, we tested olfactory memory in male and female 5xFAD mice from 3 to 15 months of age using a conditioned odour preference task. Olfactory memory was not impaired in male or female 5xFAD mice at any age tested, nor were there any sex differences. Because early-onset impairments in very long-term (remote) memory have been reported in 5xFAD mice, we trained a group of mice at 3 months of age and tested olfactory memory 90 days later. Very long-term olfactory memory in 5xFAD mice was not impaired, nor was their ability to perform the discrimination task with new odourants. Examination of brains from 5xFAD mice confirmed extensive Aβ-plaque deposition spanning the olfactory memory system, including the olfactory bulb, hippocampus, amygdala and piriform cortex. Overall this study indicates that male and female 5xFAD mice do not develop olfactory memory deficits, despite extensive Aβ deposition within the olfactory-memory regions of the brain.

  • whisker exploration behaviours in the 5xFAD Mouse are affected by sex and retinal degeneration
    Genes Brain and Behavior, 2020
    Co-Authors: Robyn A Grant, Emre Fertan, Aimee A Wong, Richard E. Brown
    Abstract:

    Active whisking in mice and rats is one of the fastest behaviours known in mammals and is used to guide complex behaviours such as exploration and navigation. During object contact, whisker movements are actively controlled and undergo robust changes in timing, speed and position. This study quantifies whisker movements in 6‐7 month old male and female 5xFAD mice, and their C57/SJL F1 wildtype (WT) controls. As well as genotype, we examined sex differences and the effects of retinal degeneration (rd). Mice were filmed using a high‐speed video camera at 500fps, under infrared light while behaving freely in three tasks: object exploration, sequential object exploration and tunnel running. Measures of whisker position, amplitude, speed and asymmetry were extracted and analyzed for each task. The 5xFAD mice had significantly altered whisker angular positions, amplitude and asymmetry during object contacts and female 5xFAD mice with rd had lower mean angular positions during object contact. There were no significant effects of genotype on sequential object exploration or on tunnel running but differences due to sex and rd were found in both tasks, with female mice making larger and faster whisker movements overall, and mice with rd making larger and faster whisker movements during object contact. There were sex differences in whisker movements during sequential object exploration and females with rd had higher whisker retraction speeds in tunnel running. These data show that measuring whisker movements can quantify genotype and sex differences and the effects of retinal degeneration during exploratory behaviour in these mice.

  • motor function deficits in the 12 month old female 5xFAD Mouse model of alzheimer s disease
    Behavioural Brain Research, 2018
    Co-Authors: Timothy P Oleary, A Robertson, Peter H Chipman, Victor F Rafuse, Richard E. Brown
    Abstract:

    Motor problems occur early in some patients with Alzheimer's disease (AD) and as the disease progresses many patients develop motor dysfunction. Motor dysfunction has been reported in some Mouse models of AD, including the 5xFAD Mouse, thus this model may be particularly useful for studying motor dysfunction in AD. In order to determine the extent of motor dysfunction in these mice, we tested 11-13 month old female 5xFAD and wildtype (WT) control mice in a battery of motor behaviour tasks. The 5xFAD mice showed hind limb clasping, weighed less and had slower righting reflexes than WT mice. In the open field, the 5xFAD mice travelled a shorter distance than the WT mice, spent less time moving and had a slower movement speed. The 5xFAD mice fell faster than the WT mice from the balance beam, wire suspension, grid suspension and rotarod tasks, indicating dysfunctions in balance, grip strength, motor co-ordination and motor learning. The 5xFAD mice had a short, shuffling gait with a shorter stride length than WT mice and had a slower swim speed. The 5xFAD mice also failed to show an acoustic startle response, likely due to motor dysfunction and previously reported hearing impairment. The 5xFAD mice did not show deficits in the ability of peripheral motor nerves to drive muscle output, suggesting that motor impairments are not due to dysfunction in peripheral motor nerves. These results indicate that the aged 5xFAD mice are deficient in numerous motor behaviours, and suggest that these mice may prove to be a good model for studying the mechanisms of motor dysfunction in AD, and motor behaviour might prove useful for assessing the efficacy of AD therapeutics. Motor dysfunction in 5xFAD mice must also be considered in behavioural tests of sensory and cognitive function so that performance is not confounded by impaired locomotor or swimming behaviour.

  • Reduced acoustic startle response and peripheral hearing loss in the 5xFAD Mouse model of Alzheimer's disease
    Genes Brain and Behavior, 2017
    Co-Authors: Timothy P. O'leary, Sooyoun Shin, Emre Fertan, Rachel N. Dingle, Awad Almuklass, Rhian K. Gunn, Jian Wang, Richard E. Brown
    Abstract:

    Hearing dysfunction has been associated with Alzheimer's disease (AD) in humans, but there is little data on the auditory function of Mouse models of AD. Furthermore, characterization of hearing ability in Mouse models is needed to ensure that tests of cognition that use auditory stimuli are not confounded by hearing dysfunction. Therefore, we assessed acoustic startle response and pre-pulse inhibition in the double transgenic 5xFAD Mouse model of AD from 3-4 to 16 months of age. The 5xFAD mice showed an age-related decline in acoustic startle as early as 3-4 months of age. We subsequently tested auditory brainstem response (ABR) thresholds at 4 and 13-14 months of age using tone bursts at frequencies of 2-32 kHz. The 5xFAD mice showed increased ABR thresholds for tone bursts between 8 and 32 kHz at 13-14 months of age. Finally, cochleae were extracted and basilar membranes were dissected to count hair cell loss across the cochlea. The 5xFAD mice showed significantly greater loss of both inner and outer hair cells at the apical and basal ends of the basilar membrane than wild-type mice at 15-16 months of age. These results indicate that the 5xFAD Mouse model of AD shows age-related decreases in acoustic startle responses, which are at least partially due to age-related peripheral hearing loss. Therefore, we caution against the use of cognitive tests that rely on audition in 5xFAD mice over 3-4 months of age, without first confirming that performance is not confounded by hearing dysfunction.

  • early detection of cerebral glucose uptake changes in the 5xFAD Mouse
    Current Alzheimer Research, 2014
    Co-Authors: Ian R Macdonald, Drew R Debay, George Andrew Reid, Timothy P Oleary, Courtney T Jollymore, George Mawko, Steven Burrell, Earl Martin, Chris V Bowen, Richard E. Brown
    Abstract:

    Brain glucose hypometabolism has been observed in Alzheimer’s disease (AD) patients, and is detected with 18 F radiolabelled glucose, using positron emission tomography. A pathological hallmark of AD is deposition of brain β- amyloid plaques that may influence cerebral glucose metabolism. The five times familial AD (5xFAD) Mouse is a model of brain amyloidosis exhibiting AD-like phenotypes. This study examines brain β-amyloid plaque deposition and 18 FDG uptake, to search for an early biomarker distinguishing 5xFAD from wild-type mice. Thus, brain 18 FDG uptake and plaque deposition was studied in these mice at age 2, 5 and 13 months. The 5xFAD mice demonstrated significantly reduced brain 18 FDG uptake at 13 months relative to wild-type controls but not in younger mice, despite substantial β- amyloid plaque deposition. However, by comparing the ratio of uptake values for glucose in different regions in the same brain, 5xFAD mice could be distinguished from controls at age 2 months. This method of measuring altered glucose metabolism may represent an early biomarker for the progression of amyloid deposition in the brain. We conclude that brain 18 FDG uptake can be a sensitive biomarker for early detection of abnormal metabolism in the 5xFAD Mouse when alternative relative uptake values are utilized.

Wenchin Huang - One of the best experts on this subject based on the ideXlab platform.

  • hdac1 modulates ogg1 initiated oxidative dna damage repair in the aging brain and alzheimer s disease
    Nature Communications, 2020
    Co-Authors: Debasis Patnaik, Ashley L Watson, Jun Wang, Chinnakkaruppan Adaikkan, Jay Penney, Wenchin Huang
    Abstract:

    DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5xFAD Mouse model of Alzheimer's disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5xFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.

  • 3d mapping reveals network specific amyloid progression and subcortical susceptibility in mice
    Communications Biology, 2019
    Co-Authors: Rebecca G Canter, Jun Wang, Wenchin Huang, Heejin Choi, Lauren Ashley Watson, Christine G Yao, Fatema Abdurrob, Stephanie M Bousleiman, Jennie Z Young, David A Bennett
    Abstract:

    Alzheimer's disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5xFAD Mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD.

Pierre Leblanc - One of the best experts on this subject based on the ideXlab platform.

  • correlation between orphan nuclear receptor nurr1 expression and amyloid deposition in 5xFAD mice an animal model of alzheimer s disease
    Journal of Neurochemistry, 2015
    Co-Authors: Minho Moon, Inhye Jeong, Pierre Leblanc
    Abstract:

    The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. Since Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer’s disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aβ accumulation, i.e., the subiculum and the frontal cortex, in the 5xFAD Mouse and that Nurr1 is highly co-expressed with Aβ at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5xFAD Mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression.

  • correlation between orphan nuclear receptor nurr1 expression and amyloid deposition in 5xFAD mice an animal model of alzheimer s disease
    Journal of Neurochemistry, 2015
    Co-Authors: Minho Moon, Pierre Leblanc, Inhye Jeong, Chunhyung Kim, Jihong Kim, Paula K J Lee, Kwangsoo Kim
    Abstract:

    The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. As Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer's disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aβ accumulation, that is, the subiculum and the frontal cortex, in the 5xFAD Mouse and that Nurr1 is highly co-expressed with Aβ at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5xFAD Mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression. Using our newly developed Nurr1-selective antibody, we show that Nurr1 protein is prominently expressed in brain areas accumulating amyloid-beta (Aβ) in the transgenic Mouse model of Alzheimer's disease (AD) and that Nurr1 is highly co-expressed with Aβ at early stages (upper panel). Furthermore, in the AD brain the number of Nurr1-expressing cells significantly declines in an age-dependent manner concomitant with increased Aβ accumulation (lower diagram) highlighting a possible Nurr1 involvement in AD pathology.

Jun Wang - One of the best experts on this subject based on the ideXlab platform.

  • hdac1 modulates ogg1 initiated oxidative dna damage repair in the aging brain and alzheimer s disease
    Nature Communications, 2020
    Co-Authors: Debasis Patnaik, Ashley L Watson, Jun Wang, Chinnakkaruppan Adaikkan, Jay Penney, Wenchin Huang
    Abstract:

    DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair to stave off functional decline remain obscure. We show that HDAC1 modulates OGG1-initated 8-oxoguanine (8-oxoG) repair in the brain. HDAC1-deficient mice display age-associated DNA damage accumulation and cognitive impairment. HDAC1 stimulates OGG1, a DNA glycosylase known to remove 8-oxoG lesions that are associated with transcriptional repression. HDAC1 deficiency causes impaired OGG1 activity, 8-oxoG accumulation at the promoters of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a similar gene set in the 5xFAD Mouse model of Alzheimer's disease. Notably, pharmacological activation of HDAC1 alleviates the deleterious effects of 8-oxoG in aged wild-type and 5xFAD mice. Our work uncovers important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration.

  • 3d mapping reveals network specific amyloid progression and subcortical susceptibility in mice
    Communications Biology, 2019
    Co-Authors: Rebecca G Canter, Jun Wang, Wenchin Huang, Heejin Choi, Lauren Ashley Watson, Christine G Yao, Fatema Abdurrob, Stephanie M Bousleiman, Jennie Z Young, David A Bennett
    Abstract:

    Alzheimer's disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5xFAD Mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD.