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Maternal Choline Supplementation as a Potential Therapy for Down Syndrome: Assessment of Effects Throughout the Lifespan

Powers, Brian E; Velazquez, Ramon; Strawderman, Myla S; Ginsberg, Stephen D; Mufson, Elliott J; Strupp, Barbara J
Maternal choline supplementation (MCS) has emerged as a promising therapy to lessen the cognitive and affective dysfunction associated with Down syndrome (DS). Choline is an essential nutrient, especially important during pregnancy due to its wide-ranging ontogenetic roles. Using the Ts65Dn mouse model of DS, our group has demonstrated that supplementing the maternal diet with additional choline (4-5 × standard levels) during pregnancy and lactation improves spatial cognition, attention, and emotion regulation in the adult offspring. The behavioral benefits were associated with a rescue of septohippocampal circuit atrophy. These results have been replicated across a series of independent studies, although the magnitude of the cognitive benefit has varied. We hypothesized that this was due, at least in part, to differences in the age of the subjects at the time of testing. Here, we present new data that compares the effects of MCS on the attentional function of adult Ts65Dn offspring, which began testing at two different ages (6 vs. 12 months of age). These data replicate and extend the results of our previous reports, showing a clear pattern indicating that MCS has beneficial effects in Ts65Dn offspring throughout life, but that the magnitude of the benefit (relative to non-supplemented offspring) diminishes with aging, possibly because of the onset of Alzheimer's disease-like neuropathology. In light of growing evidence that increased maternal choline intake during pregnancy is beneficial to the cognitive and affective functioning of all offspring (e.g., neurotypical and DS), the addition of this nutrient to a prenatal vitamin regimen would be predicted to have population-wide benefits and provide early intervention for fetuses with DS, notably including babies born to mothers unaware that they are carrying a fetus with DS.
PMID: 34690739
ISSN: 1663-4365
CID: 5042192

Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer's Disease

Alldred, Melissa J; Lee, Sang Han; Stutzmann, Grace E; Ginsberg, Stephen D
Down syndrome (DS) is the primary genetic cause of intellectual disability (ID), which is due to the triplication of human chromosome 21 (HSA21). In addition to ID, HSA21 trisomy results in a number of neurological and physiological pathologies in individuals with DS, including progressive cognitive dysfunction and learning and memory deficits which worsen with age. Further exacerbating neurological dysfunction associated with DS is the concomitant basal forebrain cholinergic neuron (BFCN) degeneration and onset of Alzheimer's disease (AD) pathology in early mid-life. Recent single population RNA sequencing (RNA-seq) analysis in the Ts65Dn mouse model of DS, specifically the medial septal cholinergic neurons of the basal forebrain (BF), revealed the mitochondrial oxidative phosphorylation pathway was significantly impacted, with a large subset of genes within this pathway being downregulated. We further queried oxidative phosphorylation pathway dysregulation in Ts65Dn mice by examining genes and encoded proteins within brain regions comprising the basocortical system at the start of BFCN degeneration (6 months of age). In select Ts65Dn mice we demonstrate significant deficits in gene and/or encoded protein levels of Complex I-V of the mitochondrial oxidative phosphorylation pathway in the BF. In the frontal cortex (Fr Ctx) these complexes had concomitant alterations in select gene expression but not of the proteins queried from Complex I-V, suggesting that defects at this time point in the BF are more severe and occur prior to cortical dysfunction within the basocortical circuit. We propose dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline onset and specifically linked to BFCN degeneration that may propagate pathology throughout cortical memory and executive function circuits in DS and AD.
PMID: 34489678
ISSN: 1663-4365
CID: 5067122

Editorial: Down Syndrome, Neurodegeneration and Dementia [Editorial]

Mufson, Elliott J; Ginsberg, Stephen D; Ma, Tao; Ledreux, Aurélie; Perez, Sylvia E
PMID: 34975462
ISSN: 1663-4365
CID: 5106782

A method for quantification of vesicular compartments within cells using 3D reconstructed confocal z-stacks: Comparison of ImageJ and Imaris to count early endosomes within basal forebrain cholinergic neurons

Gautier, Megan K; Ginsberg, Stephen D
BACKGROUND:Phenotypic changes in vesicular compartments are an early pathological hallmark of many peripheral and central diseases. For example, accurate assessment of early endosome pathology is crucial to the study of Down syndrome (DS) and Alzheimer's disease (AD), as well as other neurological disorders with endosomal-lysosomal pathology. NEW METHOD/UNASSIGNED:We describe a method for quantification of immunolabeled early endosomes within transmitter-identified basal forebrain cholinergic neurons (BFCNs) using 3-dimensional (3D) reconstructed confocal z-stacks employing Imaris software. RESULTS:Quantification of 3D reconstructed z-stacks was performed using two different image analysis programs: ImageJ and Imaris. We found ImageJ consistently overcounted the number of early endosomes present within individual BFCNs. Difficulty separating densely packed early endosomes within defined BFCNs was observed in ImageJ compared to Imaris. COMPARISON WITH EXISTING METHODS/UNASSIGNED:Previous methods quantifying endosomal-lysosomal pathology relied on confocal microscopy images taken in a single plane of focus. Since early endosomes are distributed throughout the soma and neuronal processes of BFCNs, critical insight into the abnormal early endosome phenotype may be lost as a result of analyzing only a single image of the perikaryon. Rather than relying on a representative sampling, this protocol enables precise, direct quantification of all immunolabeled vesicles within a defined cell of interest. CONCLUSIONS:Imaris is an ideal program for accurately counting punctate vesicles in the context of dual label confocal microscopy. Superior image resolution and detailed algorithms offered by Imaris make precise and rigorous quantification of individual early endosomes dispersed throughout a BFCN in 3D space readily achievable.
PMID: 33338543
ISSN: 1872-678x
CID: 4770892

Expression profiling of precuneus layer III cathepsin D-immunopositive pyramidal neurons in mild cognitive impairment and Alzheimer's disease: Evidence for neuronal signaling vulnerability

He, Bin; Perez, Sylvia E; Lee, Sang Han; Ginsberg, Stephen D; Malek-Ahmadi, Michael; Mufson, Elliott J
The precuneus (PreC; Brodmann area 7), a key hub within the default mode network (DMN) displays amyloid and tau-containing neurofibrillary tangle (NFT) pathology during the onset of Alzheimer's disease (AD). PreC layer III projection neurons contain lysosomal hydrolase cathepsin D (CatD), 14)a marker of neurons vulnerable to NFT pathology. Here we applied single population laser capture microdissection coupled with custom-designed microarray profiling to determine the genetic signature of PreC CatD-positive-layer III neurons accrued from postmortem tissue obtained from the Rush Religious Orders Study (RROS) cases with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD. Expression profiling revealed significant differential expression of key transcripts in MCI and AD compared to NCI that underlie signaling defects, including dysregulation of genes within the endosomal-lysosomal and autophagy pathways, cytoskeletal elements, AD-related genes, ionotropic and metabotropic glutamate receptors, cholinergic enzyme and receptors, markers of monoamine neurotransmission as well as steroid-related transcripts. Pervasive defects in both MCI and AD were found in select transcripts within these key gene ontology categories, underscoring the vulnerability of these corticocortical neurons during the onset and progression of dementia. Select PreC dysregulated genes detected via custom-designed microarray analysis were validated using qPCR. In summary, expression profiling of CatD positive PreC layer III neurons revealed significant dysregulation of a mosaic of genes in MCI and AD that were not previously appreciated in terms of their indication of systems-wide signaling defects in a key hub of the DMN. This article is protected by copyright. All rights reserved.
PMID: 32323319
ISSN: 1096-9861
CID: 4402282

Translational neurophysiological biomarkers of N-methyl-d-aspartate receptor dysfunction in serine racemase knockout mice

Balla, Andrea; Ginsberg, Stephen D; Abbas, Atheir I; Sershen, Henry; Javitt, Daniel C
Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-d-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. PCP led to significant increases of ASSR that were further increased in SRKO-/-, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz.
PMID: 34308374
ISSN: 2666-1446
CID: 4965432

Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease

Roy, Ethan R; Wang, Baiping; Wan, Ying-Wooi; Chiu, Gabriel; Cole, Allysa; Yin, Zhuoran; Propson, Nicholas E; Xu, Yin; Jankowsky, Joanna L; Liu, Zhandong; Lee, Virginia M-Y; Trojanowski, John Q; Ginsberg, Stephen D; Butovsky, Oleg; Zheng, Hui; Cao, Wei
Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated a potent IFN immunogenicity of nucleic acid-containing (NA-containing) amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains of multiple murine Alzheimer disease (AD) models, a phenomenon also observed in WT mouse brain challenged with generic NA-containing amyloid fibrils. In vitro, microglia innately responded to NA-containing amyloid fibrils. In AD models, activated ISG-expressing microglia exclusively surrounded NA+ amyloid β plaques, which accumulated in an age-dependent manner. Brain administration of rIFN-β resulted in microglial activation and complement C3-dependent synapse elimination in vivo. Conversely, selective IFN receptor blockade effectively diminished the ongoing microgliosis and synapse loss in AD models. Moreover, we detected activated ISG-expressing microglia enveloping NA-containing neuritic plaques in postmortem brains of patients with AD. Gene expression interrogation revealed that IFN pathway was grossly upregulated in clinical AD and significantly correlated with disease severity and complement activation. Therefore, IFN constitutes a pivotal element within the neuroinflammatory network of AD and critically contributes to neuropathogenic processes.
PMID: 31917687
ISSN: 1558-8238
CID: 4386212

The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction

Inda, Maria Carmen; Joshi, Suhasini; Wang, Tai; Bolaender, Alexander; Gandu, Srinivasa; Koren Iii, John; Che, Alicia Yue; Taldone, Tony; Yan, Pengrong; Sun, Weilin; Uddin, Mohammad; Panchal, Palak; Riolo, Matthew; Shah, Smit; Barlas, Afsar; Xu, Ke; Chan, Lon Yin L; Gruzinova, Alexandra; Kishinevsky, Sarah; Studer, Lorenz; Fossati, Valentina; Noggle, Scott A; White, Julie R; de Stanchina, Elisa; Sequeira, Sonia; Anthoney, Kyle H; Steele, John W; Manova-Todorova, Katia; Patil, Sujata; Dunphy, Mark P; Pillarsetty, NagaVaraKishore; Pereira, Ana C; Erdjument-Bromage, Hediye; Neubert, Thomas A; Rodina, Anna; Ginsberg, Stephen D; De Marco Garcia, Natalia; Luo, Wenjie; Chiosis, Gabriela
Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
PMID: 31949159
ISSN: 2041-1723
CID: 4264582

Fixation protocols for neurohistology: neurons to genes

Mufson, E J; Perez, S E; Kelley, C M; Alldred, M J; Ginsberg, S D
Since ancient times, tissue fixation for neurohistology has been an evolving area of research. Alcohol fixation first made possible examination of brain tissue specimens. In the late 1800s formaldehyde was introduced as a cross-linking fixative, which enabled histological advances. Various aldehyde solutions remain the staple for neurohistology in the neuroscience community including formalin, paraformaldehyde, glutaraldehyde, and combinations of these fixatives. A 4% paraformaldehyde solution is commonly used for numerous cytochemical procedures including tract tracing, immunohistochemistry, and in situ hybridization. A glutaraldehyde-paraformaldehyde solution is the fixative of choice for ultrastructural investigations using the electron microscope. With the advent of modern molecular and cellular biological techniques, it is now possible to isolate and study genomic DNA, RNA species, and proteins from microdissected tissue sources. Similar to light and electron microscopy, alcohol and aldehyde tissue fixation are compatible with preserving RNA integrity for regional and single cell gene array experiments using immersion- and perfusion-fixed tissue from a myriad of brain tissue sources including humans and relevant animal and cellular models.
ISSN: 1940-6045
CID: 4571842

Calorie restriction slows age-related microbiota changes in an Alzheimer's disease model in female mice

Cox, Laura M; Schafer, Marissa J; Sohn, Jiho; Vincentini, Julia; Weiner, Howard L; Ginsberg, Stephen D; Blaser, Martin J
Alzheimer's disease (AD) affects an estimated 5.8 million Americans, and advanced age is the greatest risk factor. AD patients have altered intestinal microbiota. Accordingly, depleting intestinal microbiota in AD animal models reduces amyloid-beta (Aβ) plaque deposition. Age-related changes in the microbiota contribute to immunologic and physiologic decline. Translationally relevant dietary manipulations may be an effective approach to slow microbiota changes during aging. We previously showed that calorie restriction (CR) reduced brain Aβ deposition in the well-established Tg2576 mouse model of AD. Presently, we investigated whether CR alters the microbiome during aging. We found that female Tg2576 mice have more substantial age-related microbiome changes compared to wildtype (WT) mice, including an increase in Bacteroides, which were normalized by CR. Specific gut microbiota changes were linked to Aβ levels, with greater effects in females than in males. In the gut, Tg2576 female mice had an enhanced intestinal inflammatory transcriptional profile, which was reversed by CR. Furthermore, we demonstrate that Bacteroides colonization exacerbates Aβ deposition, which may be a mechanism whereby the gut impacts AD pathogenesis. These results suggest that long-term CR may alter the gut environment and prevent the expansion of microbes that contribute to age-related cognitive decline.
PMID: 31784610
ISSN: 2045-2322
CID: 4216332