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1.
Geroscience ; 2024 May 16.
Article En | MEDLINE | ID: mdl-38755466

Aging is a primary risk factor for cognitive impairment and exacerbates multiple biological processes in the brain, including but not limited to nutrient sensing, insulin signaling, and histone deacetylation activity. Therefore, a pharmaceutical intervention of aging that targets distinct but overlapping pathways provides a basis for testing combinations of drugs as a cocktail. Our previous study showed that middle-aged mice treated with a cocktail of rapamycin, acarbose, and phenylbutyrate for 3 months had increased resilience to age-related cognitive decline. This finding provided the rationale to investigate the transcriptomic and molecular changes within the brains of mice that received this cocktail treatment or control treatment. Transcriptomic profiles were generated through ribonucleic acid (RNA) sequencing, and pathway analysis was performed by gene set enrichment analysis to evaluate the overall RNA message effect of the drug cocktail. Molecular endpoints representing aging pathways were measured using immunohistochemistry to further validate the attenuation of brain aging in the hippocampus of mice that received the cocktail treatment, each individual drug or control. Results showed that biological processes that enhance aging were suppressed, with an increased trend of autophagy in the brains of mice given the drug cocktail. The molecular endpoint assessments indicated that treatment with the drug cocktail was overall more effective than any of the individual drugs for relieving cognitive impairment by targeting multiple aging pathways.

2.
bioRxiv ; 2024 Jan 30.
Article En | MEDLINE | ID: mdl-38352353

The process of aging is defined by the breakdown of critical maintenance pathways leading to an accumulation of damage and its associated phenotypes. Aging affects many systems and is considered the greatest risk factor for a number of diseases. Therefore, interventions aimed at establishing resilience to aging should delay or prevent the onset of age-related diseases. Recent studies have shown a three-drug cocktail consisting of rapamycin, acarbose, and phenylbutyrate delayed the onset of physical, cognitive, and biological aging phenotypes in old mice. To test the ability of this drug cocktail to impact Alzheimer's disease (AD), an adeno-associated-viral vector model of AD was created. Mice were fed the drug cocktail 2 months prior to injection and allowed 3 months for phenotypic development. Cognitive phenotypes were evaluated through a spatial navigation learning task. To quantify neuropathology, immunohistochemistry was performed for AD proteins and pathways of aging. Results suggested the drug cocktail was able to increase resilience to cognitive impairment, inflammation, and AD protein aggregation while enhancing autophagy and synaptic integrity, preferentially in female cohorts. In conclusion, female mice were more susceptible to the development of early stage AD neuropathology and learning impairment, and more responsive to treatment with the drug cocktail in comparison to male mice. Translationally, a model of AD where females are more susceptible would have greater value as women have a greater burden and incidence of disease compared to men. These findings validate past results and provide the rationale for further investigations into enhancing resilience to early-stage AD by enhancing resilience to aging.

3.
bioRxiv ; 2023 Nov 21.
Article En | MEDLINE | ID: mdl-38045355

Efforts to find disease modifying treatments for Alzheimer's disease (AD) have met with limited success in part because the focus has been on testing drugs that target a specific pathogenic mechanism. Multiple pathways have been implicated in the pathogenesis of AD. Hence, the probability of more effective treatment for AD is likely increased by using an intervention that targets more than one pathway. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), as a GHK-Cu complex, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. In order to test GHK-Cu as a neurotherapeutic for AD, male and female 5xFAD transgenic mice on the C57BL/6 background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered inflammation levels in the frontal cortex and hippocampus. These observations suggest additional studies are warranted to investigate the potential of GHK-Cu peptide as a promising treatment for AD.

4.
bioRxiv ; 2023 Nov 16.
Article En | MEDLINE | ID: mdl-38014299

Infradian mood and sleep-wake rhythms with periods of 48 hr and beyond have been observed in bipolar disorder (BD) subjects that even persist in time isolation, indicating an endogenous origin. Here we show that mice exposed to methamphetamine (Meth) in drinking water develop infradian locomotor rhythms with periods of 48 hr and beyond which extend to sleep length and mania-like behaviors in support of a model for cycling in BD. This cycling capacity is abrogated upon genetic disruption of DA production in DA neurons of the ventral tegmental area (VTA) or ablation of nucleus accumbens (NAc) projecting, dopamine (DA) neurons. Chemogenetic activation of NAc-projecting DA neurons leads to locomotor period lengthening in clock deficient mice, while cytosolic calcium in DA processes of the NAc was found fluctuating synchronously with locomotor behavior. Together, our findings argue that BD cycling relies on infradian rhythm generation that depends on NAc-projecting DA neurons.

5.
Res Sq ; 2023 May 23.
Article En | MEDLINE | ID: mdl-37292694

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.

6.
Methods Mol Biol ; 2561: 3-30, 2023.
Article En | MEDLINE | ID: mdl-36399262

Human brain tissue has long been a critical resource for neuroanatomy and neuropathology, but with the advent of advanced imaging and molecular sequencing techniques, it has become possible to use human brain tissue to study, in great detail, the structural, molecular, and even functional underpinnings of human brain disease. In the century following the first description of Alzheimer's disease (AD), numerous technological advances applied to human tissue have enabled novel diagnostic approaches using diverse physical and molecular biomarkers, and many drug therapies have been tested in clinical trials (Schachter and Davis, Dialogues Clin Neurosci 2:91-100, 2000). The methods for brain procurement and tissue stabilization have remained somewhat consistently focused on formalin fixation and freezing. Although these methods have enabled research protocols of multiple modalities, new, more advanced technologies demand improved methodologies for the procurement, characterization, stabilization, and preparation of both normal and diseased human brain tissues. Here, we describe our current protocols for the procurement and characterization of fixed brain tissue, to enable systematic and precisely targeted diagnoses, and describe the novel, quantitative molecular, and neuroanatomical studies that broadly expand the use of formalin-fixed, paraffin-embedded (FFPE) tissue that will further our understanding of the mechanisms underlying human neuropathologies.


Formaldehyde , Specimen Handling , Humans , Paraffin Embedding/methods , Tissue Fixation/methods , Formaldehyde/chemistry , Brain
7.
Aging Pathobiol Ther ; 4(3): 87-89, 2022.
Article En | MEDLINE | ID: mdl-36250162

Age-related cognitive impairment (ARCI) is a neurological condition that affects millions of older people, but little is known about the increased risk of developing more severe neurodegeneration and dementia. Preclinical research is needed to understand the mechanisms of the impairment and the neuropathology associated with it. We have characterized a model of naturally occurring ARCI in the C57BL/6J mouse strain that shows an age-dependent development of cognitive impairment. As in people, some mice have little cognitive impairment while others have more severe cognitive impairment. Therefore, mice can be categorized as resistant or susceptible and the two groups can be studied for behavioral and neuropathology differences. Preliminary observations show no difference in strength and agility test scores between ARCI resistant and susceptible mice of either sex suggesting the cognitive impairment in ARCI susceptible mice is not accompanied by impairment in daily living activities, similar to ARCI in humans. The hippocampal area of the brain from ARCI susceptible mice shows evidence of an increase in the inflammatory cytokine MCP-1 compared to ARCI resistant mice, suggesting inflammation may be associated with ARCI. These preliminary observations suggest that ARCI in C57BL/6J mice could be a high-impact model to study how resilience to brain aging may predict resilience to dementia associated with Alzheimer's disease and other age-related neurological conditions.

8.
Aging Pathobiol Ther ; 4(4): 129-131, 2022.
Article En | MEDLINE | ID: mdl-36776414

The role of IGF1R signaling in the brain and its relationship to aging and neurological dysfunction is controversial. Because it was shown that low IGF1R activity consistently improved myocardial bioenergetics and function in hearts from aging mice, but not hearts from young mice, it was of interest to investigate this relationship in brain aging. We used CRISPR technology to develop a mouse model with targeted replacement of mouse IGF1R with the equivalent of the human R407H (IGF1RR407H) variant enriched in centenarians with a reduction in IGF1R protein activity. Middle-aged mice show improved cognitive performance thus possibly modeling IGF1R signaling in the aging brain, similar to what was reported in the aging heart. Because Alzheimer's disease (AD) is an age-related disease, specific IGF1RR407H pathways could be therapeutic targets in mice with AAV vector-based AD as well as for overall brain aging.

9.
Geroscience ; 43(5): 2379-2386, 2021 10.
Article En | MEDLINE | ID: mdl-34417706

Alzheimer's disease (AD) is a significant burden for human health that is increasing in prevalence as the global population ages. There is growing recognition that current preclinical models of AD are insufficient to recapitulate key aspects of the disease. Laboratory models for AD include mice, which do not naturally develop AD-like pathology during aging, and laboratory Beagle dogs, which do not share the human environment. In contrast, the companion dog shares the human environment and presents a genetically heterogeneous population of animals that might spontaneously develop age-associated AD-like pathology and cognitive dysfunction. Here, we quantitatively measured amyloid beta (Aß42 or Abeta-42) levels in three areas of the companion dog brain (prefrontal cortex, temporal cortex, hippocampus/entorhinal cortex) and cerebrospinal fluid (CSF) using a newly developed Luminex assay. We found significant positive correlations between Aß42 and age in all three brain regions. Brain Aß42 abundance in all three brain regions was also correlated with Canine Cognitive Dysfunction Scale score in a multivariate analysis. This latter effect remained significant when correcting for age, except in the temporal cortex. There was no correlation between Aß42 in CSF and cognitive scores; however, we found a significant positive correlation between Aß42 in CSF and body weight, as well as a significant negative correlation between Aß42 in CSF and age. Our results support the suitability of the companion dog as a model for AD and illustrate the utility of veterinary biobanking to make biospecimens available to researchers for analysis.


Amyloid beta-Peptides , Cognitive Dysfunction , Disease Models, Animal , Amyloid beta-Peptides/metabolism , Animals , Biological Specimen Banks , Brain/metabolism , Dogs , Peptide Fragments
10.
Mol Psychiatry ; 26(10): 5476-5480, 2021 10.
Article En | MEDLINE | ID: mdl-33972690

The hypothesis that infectious agents, particularly herpesviruses, contribute to Alzheimer's disease (AD) pathogenesis has been investigated for decades but has long engendered controversy. In the past 3 years, several studies in mouse models, human tissue models, and population cohorts have reignited interest in this hypothesis. Collectively, these studies suggest that many of the hallmarks of AD, like amyloid beta production and neuroinflammation, can arise as a protective response to acute infection that becomes maladaptive in the case of chronic infection. We place this work in its historical context and explore its etiological implications.


Alzheimer Disease , Herpesviridae , Alzheimer Disease/genetics , Amyloid beta-Peptides , Animals , Disease Models, Animal , Mice
11.
J Neurosci ; 41(15): 3512-3530, 2021 04 14.
Article En | MEDLINE | ID: mdl-33536201

The cerebellum processes neural signals related to rewarding and aversive stimuli, suggesting that the cerebellum supports nonmotor functions in cognitive and emotional domains. Catecholamines are a class of neuromodulatory neurotransmitters well known for encoding such salient stimuli. Catecholaminergic modulation of classical cerebellar functions have been demonstrated. However, a role for cerebellar catecholamines in modulating cerebellar nonmotor functions is unknown. Using biochemical methods in male mice, we comprehensively mapped TH+ fibers throughout the entire cerebellum and known precerebellar nuclei. Using electrochemical (fast scan cyclic voltammetry), and viral/genetic methods to selectively delete Th in fibers innervating the lateral cerebellar nucleus (LCN), we interrogated sources and functional roles of catecholamines innervating the LCN, which is known for its role in supporting cognition. The LCN has the most TH+ fibers in cerebellum, as well as the most change in rostrocaudal expression among the cerebellar nuclei. Norepinephrine is the major catecholamine measured in LCN. Distinct catecholaminergic projections to LCN arise only from locus coeruleus, and a subset of Purkinje cells that are positive for staining of TH. LC stimulation was sufficient to produce catecholamine release in LCN. Deletion of Th in fibers innervating LCN (LCN-Th-cKO) resulted in impaired sensorimotor integration, associative fear learning, response inhibition, and working memory in LCN-Th-cKO mice. Strikingly, selective inhibition of excitatory LCN output neurons with inhibitory designer receptor exclusively activated by designer drugs led to facilitation of learning on the same working memory task impaired in LCN-Th-cKO mice. Collectively, these data demonstrate a role for LCN catecholamines in cognitive behaviors.SIGNIFICANCE STATEMENT Here, we report on interrogating sources and functional roles of catecholamines innervating the lateral nucleus of the cerebellum (LCN). We map and quantify expression of TH, the rate-limiting enzyme in catecholamine synthesis, in the entire cerebellar system, including several precerebellar nuclei. We used cyclic voltammetry and pharmacology to demonstrate sufficiency of LC stimulation to produce catecholamine release in LCN. We used advanced viral techniques to map and selectively KO catecholaminergic neurotransmission to the LCN, and characterized significant cognitive deficits related to this manipulation. Finally, we show that inhibition of excitatory LCN neurons with designer receptor exclusively activated by designer drugs, designed to mimic Gi-coupled catecholamine GPCR signaling, results in facilitation of a working memory task impaired in LCN-specific TH KO mice.


Cerebellar Nuclei/physiology , Cognition , Norepinephrine/metabolism , Animals , Cerebellar Nuclei/cytology , Cerebellar Nuclei/metabolism , Fear , Locus Coeruleus/cytology , Locus Coeruleus/metabolism , Locus Coeruleus/physiology , Male , Memory, Short-Term , Mice , Neural Pathways/cytology , Neural Pathways/metabolism , Neural Pathways/physiology , Neurons/metabolism , Neurons/physiology , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolism
12.
Aging Pathobiol Ther ; 3(3): 77-78, 2021 Sep 30.
Article En | MEDLINE | ID: mdl-35083455

Anxiety disorders are common in older adults and are strongly associated with increased risk for numerous age-related conditions. Preclinical mechanistic data are needed to identify more specific therapeutic targets for treating and preventing these disorders. Mice serve as excellent preclinical models as they have been used extensively in aging studies, and behavioral tests have been developed. A panel of tests would capture the important clinical aspects of apathy, anxiety, and psychomotor behavior and allow longitudinal testing strategies in a rigorous and minimally stressful manner.

13.
Front Cell Neurosci ; 14: 228, 2020.
Article En | MEDLINE | ID: mdl-32848620

Tyrosine hydroxylase (Th) expression has previously been reported in Purkinje cells (PCs) of rodents and humans, but its role in the regulation of behavior is not understood. Catecholamines are well known for facilitating cognitive behaviors and are expressed in many regions of the brain. Here, we investigated a possible role in cognitive behaviors of PC catecholamines, by mapping and testing functional roles of Th positive PCs in mice. Comprehensive mapping analyses revealed a distinct population of Th expressing PCs primarily in the posterior and lateral regions of the cerebellum (comprising about 18% of all PCs). To identify the role of PC catecholamines, we selectively knocked out Th in PCs using a conditional knockout approach, by crossing a Purkinje cell-selective Cre recombinase line, Pcp2-Cre, with a floxed tyrosine hydroxylase mouse line (Thlox/lox) to produce Pcp2-Cre;Thlox/lox mice. This manipulation resulted in approximately 50% reduction of Th protein expression in the cerebellar cortex and lateral cerebellar nucleus, but no reduction of Th in the locus coeruleus, which is known to innervate the cerebellum in mice. Pcp2-Cre;Thlox/lox mice showed impairments in behavioral flexibility, response inhibition, social recognition memory, and associative fear learning relative to littermate controls, but no deficits in gross motor, sensory, instrumental learning, or sensorimotor gating functions. Catecholamines derived from specific populations of PCs appear to support cognitive functions, and their spatial distribution in the cerebellum suggests that they may underlie patterns of activation seen in human studies on the cerebellar role in cognitive function.

14.
J Interferon Cytokine Res ; 40(9): 433-437, 2020 09.
Article En | MEDLINE | ID: mdl-32790488

The essential scope of the coronavirus infectious disease 2019 (COVID-19) pandemic is focused on developing effective treatments and vaccines for acute SARS-CoV-2 infection. There is also a critical need to develop interventions to prevent the complications of COVID-19, which occur with an alarming frequency in older adults. Since severe pathologic effects of infection occur with increasing age, COVID-19 falls under the geroscience concept that all diseases in older adults have a common and major underlying cause of declining function and resilience. Geroscience posits that manipulation of aging will simultaneously delay the appearance or severity of major diseases because they share the same risk factor: aging and the multiple processes involved in aging. Drug combinations that target multiple aging processes and the cytokine networks associated with them would not necessarily limit SARS-CoV-2 infection rates but would prevent severe pathologic consequences of the disease in older adults by maintaining a more youthful-like resilience to infection-related complications. A drug cocktail aimed at controlling cytokine actions would complement current clinical treatments and vaccine effectiveness for COVID-19 and serve as a prototype for future age-related infectious disease pandemics wherein the elderly population is especially vulnerable.


Aging/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Aging/physiology , Betacoronavirus , COVID-19 , Cytokines/blood , Humans , Pandemics , Physical Fitness/physiology , SARS-CoV-2
15.
Exp Neurol ; 333: 113427, 2020 11.
Article En | MEDLINE | ID: mdl-32735872

The dopamine (DA) D2-like receptor (D2R) agonist ropinirole is often used for early and middle stage Parkinson's disease (PD). However, this D2-like agonism-based strategy has a complicating problem: D2-like agonism may activate D2 autoreceptors on the residual DA neurons in the PD brain, potentially inhibiting these residual DA neurons and motor function. We have examined this possibility by using systemic and local drug administration in transcription factor Pitx3 null mutant (Pitx3Null) mice that mimic the DA denervation in early and middle stage PD and in DA neuron tyrosine hydroxylase (TH) gene knockout (KO) mice that mimic the severe DA loss in late stage PD. We found that in Pitx3Null mice with residual DA neurons and normal mice with normal DA system, systemically injected ropinirole inhibited locomotion, whereas bilateral dorsal striatal-microinjected ropinirole stimulated movement in Pitx3Null mice; bilateral microinjection of ropinirole into the ventral tegmental area also inhibited movement in Pitx3Null mice; we further determined that ropinirole inhibited nigral DA neuron spike firing in WT mice. In contrast, both systemically and striatum-locally administered ropinirole increased movements in TH KO mice, but produced relatively more dyskinesia than L-dopa. Although requiring confirmation in non-human primates and PD patients, these data suggest that while activating D2-like receptors in striatal projection neurons and hence stimulating movements, D2-like agonists can inhibit residual DA neurons and cause akinesia when the residual DA neurons and motor functions are still substantial, and this motor-inhibitory effect disappears when almost all DA neurons are lost such as in late stage PD.


Antiparkinson Agents/pharmacology , Dopaminergic Neurons/pathology , Indoles/pharmacology , Movement Disorders/drug therapy , Parkinson Disease, Secondary/drug therapy , Animals , Antiparkinson Agents/administration & dosage , Homeodomain Proteins/genetics , Indoles/administration & dosage , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microinjections , Motor Activity/drug effects , Parkinson Disease, Secondary/physiopathology , Receptors, Dopamine D2/drug effects , Transcription Factors/genetics , Tyrosine 3-Monooxygenase/genetics , Ventral Tegmental Area
16.
Curr Protoc Mouse Biol ; 10(1): e68, 2020 Mar.
Article En | MEDLINE | ID: mdl-32096920

Current preclinical cognitive assessments are highly time intensive, with lengthy assessment procedures. In this regard, a single-day assay that focuses just on assessing learning behavior in a time-effective and relatable manner would be of value. This article describes the box maze as a short-term behavioral procedure to measure learning in mice. The protocol consists of allowing mice to explore an enclosed space that has eight holes. One of these holes leads to a tunnel that connects to an escape cage, and the latency to enter this escape hole is recorded for each mouse. Mice are tested four times within a single day, and the decrease in escape latency over time is used as a measure of learning. Age is a factor that affects escape latency in the box maze. Hence, the box-maze procedure is proposed as an efficient test to probe aging and aging intervention-related research questions. © 2020 by John Wiley & Sons, Inc.


Aging , Ethology/methods , Maze Learning , Models, Animal , Psychology/methods , Animals , Cognitive Aging , Humans , Male , Mice , Mice, Inbred C57BL
17.
PLoS One ; 15(1): e0227667, 2020.
Article En | MEDLINE | ID: mdl-31978088

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet the expression of APOE is not clearly understood. For example, it is unclear whether AD patients have elevated or decreased APOE expression or why the correlation levels of APOE RNA and the ApoE protein differ across studies. Likewise, APOE has a single CpG island (CGI) that overlaps with its 3'-exon, and this CGI's effect is unknown. We previously reported that the APOE CGI is highly methylated in human postmortem brain (PMB) and that this methylation is altered in AD frontal lobe. In this study, we comprehensively characterized APOE RNA transcripts and correlated levels of RNA expression with DNA methylation levels across the APOE CGI. We discovered the presence of APOE circular RNA (circRNA) and found that circRNA and full-length mRNA each constitute approximately one third of the total APOE RNA, with truncated mRNAs likely constituting some of the missing fraction. All APOE RNA species demonstrated significantly higher expression in AD frontal lobe than in control frontal lobe. Furthermore, we observed a negative correlation between the levels of total APOE RNA and DNA methylation at the APOE CGI in the frontal lobe. When stratified by disease status, this correlation was strengthened in controls but not in AD. Our findings suggest a possible modified mechanism of gene action for APOE in AD that involves not only the protein isoforms but also an epigenetically regulated transcriptional program driven by DNA methylation in the APOE CGI.


Alzheimer Disease/genetics , Apolipoproteins E/genetics , Brain/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Apolipoproteins E/metabolism , Autopsy , Case-Control Studies , Cerebellum/metabolism , CpG Islands , DNA Methylation , Female , Frontal Lobe/metabolism , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Male , Polymorphism, Single Nucleotide , RNA, Circular/genetics , RNA, Circular/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
18.
Hum Mol Genet ; 29(3): 495-505, 2020 02 01.
Article En | MEDLINE | ID: mdl-31943011

Aggregates of Aß peptide and the microtubule-associated protein tau are key molecular hallmarks of Alzheimer's disease (AD). However, the interaction between these two pathologies and the mechanisms underlying disease progression have remained unclear. Numerous failed clinical trials suggest the necessity for greater mechanistic understanding in order to refine strategies for therapeutic discovery and development. To this end, we have generated a transgenic Caenorhabditis elegans model expressing both human Aß1-42 peptide and human tau protein pan-neuronally. We observed exacerbated behavioral dysfunction and age-dependent neurodegenerative changes in the Aß;tau transgenic animals. Further, these changes occurred in the Aß;tau transgenic animals at greater levels than worms harboring either the Aß1-42 or tau transgene alone and interestingly without changes to the levels of tau expression, phosphorylation or aggregation. Functional changes were partially rescued with the introduction of a genetic suppressor of tau pathology. Taken together, the data herein support a synergistic role for both Aß and tau in driving neuronal dysfunction seen in AD. Additionally, we believe that the utilization of the genetically tractable C. elegans model will provide a key resource for dissecting mechanisms driving AD molecular pathology.


Amyloid beta-Peptides/adverse effects , Disease Models, Animal , Neurodegenerative Diseases/pathology , Neurons/pathology , tau Proteins/metabolism , Animals , Animals, Genetically Modified , Caenorhabditis elegans , Humans , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/metabolism , Neurons/metabolism , Phosphorylation , tau Proteins/genetics
19.
Trends Biomed Res ; 3(1)2020 Dec.
Article En | MEDLINE | ID: mdl-37113577

An insulin-like growth factor-1 receptor (IGF1R) variant in exon 6 (Arg-407-His) in Ashkenazi Jewish centenarians was previously found to be associated with reduced IGF1R activity. To further study this longevity associated IGF1R variant, we generated a novel mouse line carrying the R407H variant in exon 6 of the Igf1r gene by employing CRISPR/Cas9 genome editing technology. Here, we show that the Igf1r gene can be edited in mouse embryos by zygotic electroporation of Cas9 protein and a single-guide RNAs together with a single stranded oligonucleotide donor containing the desired key nucleotide changes at the Igf1r locus. Sequence analysis of F0 and F1 mice following targeted editing demonstrated the robustness of this approach in mice using CRISPR/Cas9 directed homologous recombination (HDR). Western blot analysis indicates that mice heterozygous for the variant have a significant decrease in IGF1R phosphorylation in various tissues, including skeletal muscle, compared to wildtype. In addition, depletion of IGF1R signaling specifically in skeletal muscle of progeroid Ercc1 -/Δ mice resulted in extended health span and median lifespan providing the rationale for long term lifespan studies in Igf1r hR407H variant mice. This mouse line will be a valuable genetic tool to help determine the impact of IGF1R signaling on aging and longevity. The CRISPR editing approach represents a prototype for generating additional longevity associated gene variant mouse lines to study relevance to human exceptional longevity.

20.
Nat Commun ; 10(1): 4923, 2019 10 29.
Article En | MEDLINE | ID: mdl-31664021

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.


Hippocampus/metabolism , Hypothalamic Area, Lateral/metabolism , Hypothalamic Hormones/metabolism , Impulsive Behavior , Melanins/metabolism , Pituitary Hormones/metabolism , Animals , Hypothalamic Hormones/genetics , Male , Melanins/genetics , Neural Pathways , Neurons/metabolism , Nucleus Accumbens/metabolism , Pituitary Hormones/genetics , Rats , Rats, Sprague-Dawley , Receptors, Somatostatin/genetics , Receptors, Somatostatin/metabolism
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