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1.
Aging Cell ; 22(4): e13787, 2023 04.
Article in English | MEDLINE | ID: mdl-36734122

ABSTRACT

Interventions for animal lifespan extension like caloric restriction (CR) have identified physiologic and biochemical pathways related to hunger and energy-sensing status as possible contributors, but mechanisms have not been fully elucidated. Prior studies using ghrelin agonists show greater food intake but no effect on lifespan in rodent models. This experiment in male C57BL/6J mice tested the influence of ghrelin agonism for perceived hunger, in the absence of CR, on longevity. Mice aged 4 weeks were allowed to acclimate for 2 weeks prior to being assigned (N = 60/group). Prior to lights off daily (12:12 cycle), animals were fed a ghrelin agonist pill (LY444711; Eli Lilly) or a placebo control (Ctrl) until death. Treatment (GhrAg) animals were pair-fed daily based on the group mean food intake consumed by Ctrl (ad libitum feeding) the prior week. Results indicate an increased lifespan effect (log-rank p = 0.0032) for GhrAg versus placebo Ctrl, which weighed significantly more than GhrAg (adjusted for baseline weight). Further studies are needed to determine the full scope of effects of this ghrelin agonist, either directly via increased ghrelin receptor signaling or indirectly via other hypothalamic, systemic, or tissue-specific mechanisms.


Subject(s)
Ghrelin , Longevity , Animals , Male , Mice , Caloric Restriction , Ghrelin/agonists , Mice, Inbred C57BL
2.
Front Neuroanat ; 15: 656882, 2021.
Article in English | MEDLINE | ID: mdl-33994960

ABSTRACT

It has been demonstrated that in adulthood rodents show newly born neurons in the subgranular layer (SGL) of the dentate gyrus (DG), and in the subventricular zone (SVZ). The neurons generated in the SVZ migrate through the rostral migratory stream (RMS) to the olfactory bulb. One of the markers of newly generated neurons is doublecortin (DCX). The degu similarly shows significant numbers of DCX-labeled neurons in the SGL, SVZ, and RMS. Further, most of the nuclei of these DCX-expressing neurons are also labeled by proliferating nuclear antigen (PCNA) and Ki67. Finally, whereas in rats and mice DCX-labeled neurons are predominantly present in the SGL and SVZ, with only a few DCX neurons present in piriform cortex, the degu also shows significant numbers of DCX expressing neurons in areas outside of SVZ, DG, and PC. Many areas of neocortex in degu demonstrate DCX-labeled neurons in layer II, and most of these neurons are found in the limbic cortices. The DCX-labeled cells do not stain with NeuN, indicating they are immature neurons.

3.
Brain Res ; 1746: 147022, 2020 11 01.
Article in English | MEDLINE | ID: mdl-32707043

ABSTRACT

Alzheimer's disease (AD) is the most common cause of dementia. Neuropathological processes, including the accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles, and neuroinflammation, lead to cognitive impairment at middle and eventually later stages of AD progression. Over the last decade, focused efforts have explored repurposed drug approaches for AD pathophysiological mechanisms. Recently, auranofin, an anti-inflammatory drug, was shown to have therapeutic potential in a number of diseases in addition to rheumatoid arthritis. Surprisingly, no data regarding the effects of auranofin on cognitive deficits in AD mice or the influence of auranofin on Aß pathology and neuroinflammatory processes are available. In the present study, we used 14-month-old transgenic male APPNL-G-F/NL-G-F mice to assess the effects of subchronic administration of auranofin at low doses (1 and 5 mg/kg, intraperitoneal) on spatial memory, Aß pathology and the expression of cortical and hippocampal proteins (glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule-1 (Iba-1)) and proteins related to synaptic plasticity (glutamic acid decarboxylase 67 (GAD67), homer proteins homologue-1 (Homer-1)). The data demonstrated that auranofin significantly decreased Aß deposition in the hippocampus and the number of Aß plaques in the cingulate cortex, but it did not have memory-enhancing effects or induce changes in the expression of the studied proteins. Our current results highlight the importance of considering further pre-clinical research to investigate the possible beneficial effects of auranofin on the other pathological aspects of AD.


Subject(s)
Alzheimer Disease/pathology , Anti-Inflammatory Agents/pharmacology , Auranofin/pharmacology , Brain/drug effects , Brain/pathology , Amyloid beta-Protein Precursor/toxicity , Animals , Disease Models, Animal , Male , Mice , Mice, Transgenic
4.
J Alzheimers Dis ; 66(4): 1371-1378, 2018.
Article in English | MEDLINE | ID: mdl-30412490

ABSTRACT

Aging is the leading risk factor for idiopathic Alzheimer's disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2 + dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2 + dysregulation occurs in human entorhinal neurons and promotes NFT pathogenesis.


Subject(s)
Aging/metabolism , Alzheimer Disease/metabolism , Calcium Signaling/physiology , Calcium/metabolism , Entorhinal Cortex/metabolism , Neurons/metabolism , Alzheimer Disease/pathology , Animals , Entorhinal Cortex/pathology , Male , Neurofibrillary Tangles/metabolism , Neurofibrillary Tangles/pathology , Neurons/pathology , Rats , Rats, Inbred F344
5.
Chem Commun (Camb) ; 54(26): 3294-3297, 2018 Mar 27.
Article in English | MEDLINE | ID: mdl-29537428

ABSTRACT

Pressure can shift the polymer-monomer equilibrium of Aß, increasing pressure first leads to a release of Aß-monomers, surprisingly at pressures higher than 180 MPa repolymerization is induced. By high pressure NMR spectroscopy, differences of partial molar volumes ΔV0 and compressibility factors Δß' of polymerization were determined at different temperatures. The d-enantiomeric peptides RD2 and RD2D3 bind to monomeric Aß with affinities substantially higher than those determined for fibril formation. By reducing the Aß concentration below the critical concentration for polymerization they inhibit the formation of toxic oligomers. Chemical shift perturbation allows the identification of the binding sites. The d-peptides are candidates for drugs preventing Alzheimer's disease. We show that RD2D3 has a positive effect on the cognitive behaviour of transgenic (APPSwDI) mice prone to Alzheimer's disease. The heterodimer complexes have a smaller Stokes radius than Aß alone indicating the recognition of a more compact conformation of Aß identified by high pressure NMR before.


Subject(s)
Amyloid beta-Peptides/metabolism , Peptides/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides/chemistry , Animals , Binding Sites , Dimerization , Humans , Mice , Mice, Transgenic , Nuclear Magnetic Resonance, Biomolecular , Peptides/chemistry , Peptides/therapeutic use , Protein Binding , Stereoisomerism , Thermodynamics
6.
J Neurosci ; 38(4): 1030-1041, 2018 01 24.
Article in English | MEDLINE | ID: mdl-29255009

ABSTRACT

Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca2+ release, reverses aging-induced memory impairment and neuronal Ca2+ dysregulation. Here, we tested the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13 months of age (long-term, LT) or 19 months of age (short-term, ST) and tested memory performance in the Morris water maze at 21 months of age. Aged rats treated ST or LT with FKBP1b substantially outperformed age-matched vector controls and performed similarly to each other and young controls (YCs). Transcriptional profiling in the same animals identified 2342 genes with hippocampal expression that was upregulated/downregulated in aged controls (ACs) compared with YCs (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged FKBP1b-treated rats compared with ACs, with FKBP1b restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in YCs. This inverse relationship between the aging and FKBP1b effects suggests that the aging effects arise from FKBP1b deficiency. Functional category analysis revealed that genes downregulated with aging and restored by FKBP1b were associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by FKBP1b associated primarily with glial-neuroinflammatory, ribosomal, and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction and FKBP1b-mediated restoration of neuronal microtubular structure. Therefore, a previously unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by FKBP1b overexpression.SIGNIFICANCE STATEMENT Previously, we found that hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of intracellular Ca2+ responses, reverses both aging-related Ca2+ dysregulation and cognitive impairment. Here, we tested whether hippocampal FKBP1b overexpression also counteracts aging changes in gene transcriptional networks. In addition to reducing memory deficits in aged rats, FKBP1b selectively counteracted aging-induced expression changes in 37% of aging-dependent genes, with cytoskeletal and extracellular structure categories highly associated with the FKBP1b-rescued genes. Our results indicate that, in parallel with cognitive processes, a novel transcriptional network coordinating brain structural organization is dysregulated with aging and restored by FKBP1b.


Subject(s)
Aging/physiology , Gene Expression Regulation/physiology , Hippocampus/metabolism , Memory/physiology , Tacrolimus Binding Proteins/metabolism , Animals , Calcium Signaling/physiology , Hippocampus/physiopathology , Male , Memory Disorders/physiopathology , Rats , Rats, Inbred F344 , Rats, Transgenic
7.
BMC Neurosci ; 18(1): 77, 2017 Dec 02.
Article in English | MEDLINE | ID: mdl-29197324

ABSTRACT

BACKGROUND: PDE4 cyclic nucleotide phosphodiesterases regulate 3', 5' cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions. The PDE4 isoform PDE4B1 also interacts with the DISC1 protein, implicated in neural development and behavioral disorders. The cellular functions of PDE4B1 have been investigated extensively, but its function(s) in the intact organism remained unexplored. RESULTS: To specifically disrupt PDE4B1, we developed mice that express a PDE4B1-D564A transgene in the hippocampus and forebrain. The transgenic mice showed enhanced phosphorylation of CREB and ERK1/2 in hippocampus. Hippocampal neurogenesis was increased in the transgenic mice. Hippocampal electrophysiological studies showed increased baseline synaptic transmission and enhanced LTP in male transgenic mice. Behaviorally, male transgenic mice showed increased activity in prolonged open field testing, but neither male nor female transgenic mice showed detectable anxiety-like behavior or antidepressant effects in the elevated plus-maze, tail-suspension or forced-swim tests. Neither sex showed any significant differences in associative fear conditioning or showed any demonstrable abnormalities in pre-pulse inhibition. CONCLUSIONS: These data support the use of an isoform-selective approach to the study of PDE4B1 function in the CNS and suggest a probable role of PDE4B1 in synaptic plasticity and behavior. They also provide additional rationale and a refined approach to the development of small-molecule PDE4B1-selective inhibitors, which have potential functions in disorders of cognition, memory, mood and affect.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Hippocampus/metabolism , Long-Term Potentiation/physiology , Motor Activity/physiology , Neurogenesis/physiology , Synaptic Transmission/physiology , Animals , Anxiety/metabolism , Association Learning/physiology , Conditioning, Psychological/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Depression/metabolism , Fear/physiology , Female , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Memory/physiology , Mice, Transgenic , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Mutation , Phosphorylation/physiology
8.
Sci Rep ; 7(1): 16275, 2017 11 24.
Article in English | MEDLINE | ID: mdl-29176708

ABSTRACT

While amyloid-ß protein (Aß) aggregation into insoluble plaques is one of the pathological hallmarks of Alzheimer's disease (AD), soluble oligomeric Aß has been hypothesized to be responsible for synapse damage, neurodegeneration, learning, and memory deficits in AD. Here, we investigate the in vitro and in vivo efficacy of the D-enantiomeric peptide RD2, a rationally designed derivative of the previously described lead compound D3, which has been developed to efficiently eliminate toxic Aß42 oligomers as a promising treatment strategy for AD. Besides the detailed in vitro characterization of RD2, we also report the results of a treatment study of APP/PS1 mice with RD2. After 28 days of treatment we observed enhancement of cognition and learning behaviour. Analysis on brain plaque load did not reveal significant changes, but a significant reduction of insoluble Aß42. Our findings demonstrate that RD2 was significantly more efficient in Aß oligomer elimination in vitro compared to D3. Enhanced cognition without reduction of plaque pathology in parallel suggests that synaptic malfunction due to Aß oligomers rather than plaque pathology is decisive for disease development and progression. Thus, Aß oligomer elimination by RD2 treatment may be also beneficial for AD patients.


Subject(s)
Plaque, Amyloid/pathology , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Cognition/drug effects , Disease Models, Animal , Female , Mice , Peptides/chemistry , Peptides/therapeutic use , Plaque, Amyloid/drug therapy
9.
ACS Chem Neurosci ; 8(9): 1889-1900, 2017 09 20.
Article in English | MEDLINE | ID: mdl-28581708

ABSTRACT

Amyloid-beta (Aß) oligomers are thought to be causative for the development and progression of Alzheimer's disease (AD). Starting from the Aß oligomer eliminating d-enantiomeric peptide D3, we developed and applied a two-step procedure based on peptide microarrays to identify D3 derivatives with increased binding affinity and specificity for monomeric Aß(1-42) to further enhance the Aß oligomer elimination efficacy. Out of more than 1000 D3 derivatives, we selected seven novel d-peptides, named ANK1 to ANK7, and characterized them in more detail in vitro. All ANK peptides bound to monomeric Aß(1-42), eliminated Aß(1-42) oligomers, inhibited Aß(1-42) fibril formation, and reduced Aß(1-42)-induced cytotoxicity more efficiently than D3. Additionally, ANK6 completely inhibited the prion-like propagation of preformed Aß(1-42) seeds and showed a nonsignificant tendency for improving memory performance of tg-APPSwDI mice after i.p. application for 4 weeks. This supports the hypothesis that stabilization of Aß monomers and thereby induced elimination of Aß oligomers is a suitable therapeutic strategy.


Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Neuroprotective Agents/pharmacology , Nootropic Agents/pharmacology , Oligopeptides/pharmacology , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Amyloid beta-Peptides/toxicity , Amyloid beta-Peptides/ultrastructure , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Animals, Genetically Modified , Binding, Competitive , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Female , Humans , Mice, Inbred C57BL , Microarray Analysis , Peptide Fragments/toxicity , Peptide Fragments/ultrastructure , Plaque, Amyloid/drug therapy , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Presenilin-1/genetics , Presenilin-1/metabolism , Protein Aggregation, Pathological/drug therapy , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/pathology , Recombinant Proteins/metabolism , Recombinant Proteins/toxicity , Recombinant Proteins/ultrastructure
10.
Neurobiol Learn Mem ; 141: 209-216, 2017 May.
Article in English | MEDLINE | ID: mdl-28458035

ABSTRACT

Preterm infants exposed to supra-physiological levels of oxygen often have poor executive and memory function associated with reductions in hippocampal volume later in life. We recently showed that adult mice exposed to neonatal hyperoxia have deficits in spatial navigation and increased exploratory behavior associated with hippocampal shrinkage. Retinoids attenuate hyperoxia-induced lung injury in animal models and reduce neonatal chronic lung disease in preterm infants. We hypothesized that retinoid (combination of Vitamin A+Retinoic Acid [VARA]) administration in mice during neonatal hyperoxia would attenuate oxygen-induced cognitive impairment when assessed in adult life. C57BL/6 mouse pups were exposed to hyperoxia (85% oxygen) or air (21% oxygen), in combination with VARA or canola oil (Vehicle) from postnatal day 2 to 14 and then returned to air. Neurobehavioral (Morris water maze, open field and zero maze tests), structural assessments (MRI and histology), and hippocampal protein measurements were performed. Neonatal hyperoxia resulted in spatial navigation deficits and increased exploratory behavior and accompanied by hippocampal shrinkage in adults, all of which were attenuated by VARA administration. During hyperoxia, VARA increased hippocampal phosphorylated and total mammalian target of rapamycin, and synaptophysin levels to a greater extent in hyperoxia compared to normoxia. In conclusion, VARA attenuated neonatal hyperoxia-induced neurobehavioral impairment and associated reductions in hippocampal volume in adult mice, possibly by increasing mTOR signaling and synaptic density. These novel data suggest that retinoids may be neuroprotective in extremely preterm infants at high risk of impairment, and may potentially be effective in other models of oxidant stress as well.


Subject(s)
Behavior, Animal/drug effects , Cognitive Dysfunction/drug therapy , Hippocampus/drug effects , Hyperoxia/complications , Tretinoin/pharmacology , Vitamin A/pharmacology , Animals , Animals, Newborn , Cognition/drug effects , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , Hippocampus/diagnostic imaging , Hippocampus/metabolism , Maze Learning/drug effects , Mice , Phosphorylation/drug effects , Signal Transduction/drug effects , Spatial Navigation/drug effects , Synaptophysin/metabolism , TOR Serine-Threonine Kinases/metabolism , Tretinoin/therapeutic use , Vitamin A/therapeutic use
11.
Eur J Clin Invest ; 46(12): 985-993, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27711975

ABSTRACT

BACKGROUND: Differing opinions exist on whether associations obtained in observational studies can be reliable indicators of a causal effect if the observational study is sufficiently well controlled and executed. MATERIALS AND METHODS: To test this, we conducted two animal observational studies that were rigorously controlled and executed beyond what is achieved in studies of humans. In study 1, we randomized 332 genetically identical C57BL/6J mice into three diet groups with differing food energy allotments and recorded individual self-selected daily energy intake and lifespan. In study 2, 60 male mice (CD1) were paired and divided into two groups for a 2-week feeding regimen. We evaluated the association between weight gain and food consumption. Within each pair, one animal was randomly assigned to an S group in which the animals had free access to food. The second paired animal (R group) was provided exactly the same diet that their S partner ate the day before. RESULTS: In study 1, across all three groups, we found a significant negative effect of energy intake on lifespan. However, we found a positive association between food intake and lifespan among the ad libitum feeding group: 29·99 (95% CI: 8·2-51·7) days per daily kcal. In study 2, we found a significant (P = 0·003) group (randomized vs. self-selected)-by-food consumption interaction effect on weight gain. CONCLUSION: At least in nutrition research, associations derived from observational studies may not be reliable indicators of causal effects, even with the most rigorous study designs achievable.


Subject(s)
Causality , Eating , Energy Intake , Longevity , Weight Gain , Animals , Feeding Behavior , Female , Male , Mice , Mice, Inbred C57BL , Observational Studies as Topic , Random Allocation , Research Design
12.
Biochim Biophys Acta ; 1858(11): 2717-2724, 2016 11.
Article in English | MEDLINE | ID: mdl-27423267

ABSTRACT

The application of small peptides targeting amyloid beta (Aß) is one of many drug development strategies for the treatment of Alzheimer's disease (AD). We have previously identified several peptides consisting solely of D-enantiomeric amino acid residues obtained from mirror-image phage display selection, which bind to Aß in different assembly states and eliminate toxic Aß aggregates. Some of these D-peptides show both diagnostic and therapeutic potential in vitro and in vivo. Here we have analysed the similarity of the arginine-rich D-peptide D3 to the arginine-rich motif (ARM) of the human immunodeficiency virus type 1 transactivator of transcription (HIV-Tat) protein, and examined its in vivo blood-brain barrier (BBB) permeability using wild type mice and transgenic mouse models of Alzheimer's disease. We are able to demonstrate that D3 rapidly enters the brain where it can be found associated with amyloid plaques suggesting a direct penetration of BBB.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/chemistry , Blood-Brain Barrier/drug effects , Neuroprotective Agents/pharmacokinetics , Oligopeptides/metabolism , Administration, Oral , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amino Acid Sequence , Amyloid beta-Peptides/metabolism , Animals , Blood-Brain Barrier/metabolism , Brain/drug effects , Brain/metabolism , Capillary Permeability , Disease Models, Animal , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/metabolism , Oligopeptides/chemical synthesis , Oligopeptides/pharmacokinetics , Sequence Alignment , tat Gene Products, Human Immunodeficiency Virus/chemistry
13.
Pharmacol Res ; 113(Pt B): 781-787, 2016 11.
Article in English | MEDLINE | ID: mdl-27345857

ABSTRACT

The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD.


Subject(s)
Alzheimer Disease/drug therapy , Calcium Channel Blockers/pharmacology , Calcium/metabolism , Gyrus Cinguli/drug effects , Hippocampus/drug effects , Memory/drug effects , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Animals , Anti-Anxiety Agents/pharmacology , Blood-Brain Barrier/metabolism , Dihydropyridines/pharmacology , Disease Models, Animal , Female , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , Glutamate Decarboxylase/metabolism , Gyrus Cinguli/metabolism , Hippocampus/metabolism , Male , Maze Learning/drug effects , Mice , Mice, Transgenic , Neuronal Plasticity/drug effects , Up-Regulation/drug effects , Vesicular Inhibitory Amino Acid Transport Proteins/metabolism
14.
ACS Chem Neurosci ; 7(8): 1088-96, 2016 08 17.
Article in English | MEDLINE | ID: mdl-27240424

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common type of dementia. Until now, there is no curative therapy available. Previously, we selected the amyloid-beta (Aß) targeting peptide D3 consisting of 12 d-enantiomeric amino acid residues by mirror image phage display as a potential drug candidate for the treatment of AD. In the current approach, we investigated the optimization potential of linear D3 with free C-terminus (D3COOH) by chemical modifications. First, the impact of the net charge was investigated and second, cyclization was introduced which is a well-known tool for the optimization of peptides for enhanced target affinity. Following this strategy, three D3 derivatives in addition to D3COOH were designed: C-terminally amidated linear D3 (D3CONH2), cyclic D3 (cD3), and cyclic D3 with an additional arginine residue (cD3r) to maintain the net charge of linear D3CONH2. These four compounds were compared to each other according to their binding affinities to Aß(1-42), their efficacy to eliminate cytotoxic oligomers, and consequently their potency to neutralize Aß(1-42) oligomer induced neurotoxicity. D3CONH2 and cD3r versions with equally increased net charge showed superior properties over D3COOH and cD3, respectively. The cyclic versions showed superior properties compared to their linear version with equal net charge, suggesting cD3r to be the most efficient compound among these four. Indeed, treatment of the transgenic AD mouse model Tg-SwDI with cD3r significantly enhanced spatial memory and cognition of these animals as revealed by water maze performance. Therefore, charge increase and cyclization imply suitable modification steps for an optimization approach of the Aß targeting compound D3.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/toxicity , Peptide Fragments/metabolism , Peptide Fragments/toxicity , Peptides, Cyclic/chemistry , Peptides, Cyclic/therapeutic use , Alzheimer Disease/complications , Alzheimer Disease/genetics , Amyloid beta-Peptides/ultrastructure , Amyloid beta-Protein Precursor/genetics , Animals , Cell Line, Tumor , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Cytokines/metabolism , Disease Models, Animal , Humans , Male , Maze Learning/drug effects , Mice, Inbred C57BL , Mice, Transgenic , Molecular Conformation/drug effects , Mutation/genetics , Neuroblastoma/pathology , Oligopeptides/chemistry , Peptide Fragments/ultrastructure , Peptides, Cyclic/metabolism , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Plaque, Amyloid/ultrastructure , Protein Binding/drug effects , Stereoisomerism
15.
Exp Gerontol ; 86: 39-49, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27167583

ABSTRACT

Clinical and epidemiological evidence suggests that lifestyle factors, including nutrition, may influence the chances of developing of Alzheimer's disease (AD), and also likely affect the aging process. Whereas it is clear that high-fat diets are increasing both body weight and the risk of developing Alzheimer's disease, to date, there have been very few studies comparing diets high with different sources of calories (i.e., high fat versus high protein versus high carbohydrates) to determine whether dietary composition has importance beyond the known effect of high caloric intake to increase body weight, AD pathology and cognitive deficits. In the current study we examined the effects that different diets high in carbohydrate, protein or fat content, but similar in caloric value, have on the development of cognitive impairment and brain pathology in wild-type and Tg AD model mice. The results demonstrate that long term feeding with balanced diets similar in caloric content but with significant changes in the source of calories, all negatively influence cognition compared to the control diet, and that this effect is more pronounced in Tg animals with AD pathology.


Subject(s)
Alzheimer Disease/etiology , Cognition Disorders/etiology , Diet/adverse effects , Dietary Carbohydrates/pharmacology , Dietary Fats/pharmacology , Dietary Proteins/pharmacology , Adiposity/physiology , Alzheimer Disease/pathology , Analysis of Variance , Animals , Behavior, Animal/physiology , Body Composition/physiology , Body Weight/physiology , Brain/pathology , Cognition Disorders/pathology , Diet, High-Fat/adverse effects , Disease Models, Animal , Energy Intake/physiology , Male , Mice, Transgenic
16.
Hum Mol Genet ; 25(8): 1619-36, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-26908599

ABSTRACT

Identifying molecular drivers of pathology provides potential therapeutic targets. Differentiating between drivers and coincidental molecular alterations presents a major challenge. Variation unrelated to pathology further complicates transcriptomic, proteomic and metabolomic studies which measure large numbers of individual molecules. To overcome these challenges towards the goal of determining drivers of Huntington's disease (HD), we generated an allelic series of HD knock-in mice with graded levels of phenotypic severity for comparison with molecular alterations. RNA-sequencing analysis of this series reveals high numbers of transcripts with level alterations that do not correlate with phenotypic severity. These discorrelated molecular changes are unlikely to be drivers of pathology allowing an exclusion-based strategy to provide a short list of driver candidates. Further analysis of the data shows that a majority of transcript level changes in HD knock-in mice involve alteration of the rate of mRNA processing and/or degradation rather than solely being due to alteration of transcription rate. The overall strategy described can be applied to assess the influence of any molecular change on pathology for diseases where different mutations cause graded phenotypic severity.


Subject(s)
Gene Expression Regulation , Gene Knock-In Techniques/methods , Huntington Disease/pathology , RNA, Messenger/metabolism , Alleles , Animals , Disease Models, Animal , Humans , Huntington Disease/genetics , Mice , Phenotype , Sequence Analysis, RNA
17.
Sci Rep ; 5: 13222, 2015 Sep 23.
Article in English | MEDLINE | ID: mdl-26394756

ABSTRACT

Strong evidence exists for a central role of amyloid ß-protein (Aß) oligomers in the pathogenesis of Alzheimer's disease. We have developed a fast, reliable and robust in vitro assay, termed QIAD, to quantify the effect of any compound on the Aß aggregate size distribution. Applying QIAD, we studied the effect of homotaurine, scyllo-inositol, EGCG, the benzofuran derivative KMS88009, ZAß3W, the D-enantiomeric peptide D3 and its tandem version D3D3 on Aß aggregation. The predictive power of the assay for in vivo efficacy is demonstrated by comparing the oligomer elimination efficiency of D3 and D3D3 with their treatment effects in animal models of Alzheimer´s disease.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/analysis , Amyloid beta-Peptides/metabolism , Protein Aggregation, Pathological/drug therapy , Animals , Carrier Proteins/pharmacology , Catechin/analogs & derivatives , Catechin/pharmacology , Disease Models, Animal , Ferredoxin-NADP Reductase/pharmacology , Humans , Inositol/pharmacology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Oligopeptides/pharmacology , Taurine/analogs & derivatives , Taurine/pharmacology
18.
J Neurosci ; 35(30): 10878-87, 2015 Jul 29.
Article in English | MEDLINE | ID: mdl-26224869

ABSTRACT

Brain Ca2+ regulatory processes are altered during aging, disrupting neuronal, and cognitive functions. In hippocampal pyramidal neurons, the Ca2+ -dependent slow afterhyperpolarization (sAHP) exhibits an increase with aging, which correlates with memory impairment. The increased sAHP results from elevated L-type Ca2+ channel activity and ryanodine receptor (RyR)-mediated Ca2+ release, but underlying molecular mechanisms are poorly understood. Previously, we found that expression of the gene encoding FK506-binding protein 12.6/1b (FKBP1b), a small immunophilin that stabilizes RyR-mediated Ca2+ release in cardiomyocytes, declines in hippocampus of aged rats and Alzheimer's disease subjects. Additionally, knockdown/disruption of hippocampal FKBP1b in young rats augments neuronal Ca2+ responses. Here, we test the hypothesis that declining FKBP1b underlies aging-related hippocampal Ca2+ dysregulation. Using microinjection of adeno-associated viral vector bearing a transgene encoding FKBP1b into the hippocampus of aged male rats, we assessed the critical prediction that overexpressing FKBP1b should reverse Ca2+ -mediated manifestations of brain aging. Immunohistochemistry and qRT-PCR confirmed hippocampal FKBP1b overexpression 4-6 weeks after injection. Compared to aged vector controls, aged rats overexpressing FKBP1b showed dramatic enhancement of spatial memory, which correlated with marked reduction of sAHP magnitude. Furthermore, simultaneous electrophysiological recording and Ca2+ imaging in hippocampal neurons revealed that the sAHP reduction was associated with a decrease in parallel RyR-mediated Ca2+ transients. Thus, hippocampal FKBP1b overexpression reversed key aspects of Ca2+ dysregulation and cognitive impairment in aging rats, supporting the novel hypothesis that declining FKBP1b is a molecular mechanism underlying aging-related Ca2+ dysregulation and unhealthy brain aging and pointing to FKBP1b as a potential therapeutic target. SIGNIFICANCE STATEMENT: This paper reports critical tests of a novel hypothesis that proposes a molecular mechanism of unhealthy brain aging and possibly, Alzheimer's disease. For more than 30 years, evidence has been accumulating that brain aging is associated with dysregulation of calcium in neurons. Recently, we found that FK506-binding protein 12.6/1b (FKBP1b), a small protein that regulates calcium, declines with aging in the hippocampus, a brain region important for memory. Here we used gene therapy approaches and found that raising FKBP1b reversed calcium dysregulation and memory impairment in aging rats, allowing them to perform a memory task as well as young rats. These studies identify a potential molecular mechanism of brain aging and may also have implications for treatment of Alzheimer's disease.


Subject(s)
Aging/physiology , Calcium/metabolism , Cognition/physiology , Neurons/metabolism , Tacrolimus Binding Proteins/metabolism , Animals , Cognition Disorders/etiology , Cognition Disorders/metabolism , Hippocampus/metabolism , Immunohistochemistry , Male , Patch-Clamp Techniques , Rats , Rats, Inbred F344 , Rats, Transgenic , Real-Time Polymerase Chain Reaction , Transgenes
19.
Sci Rep ; 5: 11452, 2015 Jun 19.
Article in English | MEDLINE | ID: mdl-26090621

ABSTRACT

The orexigenic hormone ghrelin, a potential antagonist of the insulin system, ensures sufficient serum glucose in times of fasting. In the race for new therapeutics for diabetes, one focus of study has been antagonizing the ghrelin system in order to improve glucose tolerance. We provide evidence for a differential role of a ghrelin agonist on glucose homeostasis in an Alzheimer's disease mouse model fed a high-glycemic index diet as a constant challenge for glucose homeostasis. The ghrelin agonist impaired glucose tolerance immediately after administration but not in the long term. At the same time, the ghrelin agonist improved spatial learning in the mice, raised their activity levels, and reduced their body weight and fat mass. Immunoassay results showed a beneficial impact of long-term treatment on insulin signaling pathways in hippocampal tissue. The present results suggest that ghrelin might improve cognition in Alzheimer's disease via a central nervous system mechanism involving insulin signaling.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/psychology , Cognition , Ghrelin/agonists , Insulin Resistance , Insulin/metabolism , Animals , Blood Glucose/drug effects , Body Weight/drug effects , Cognition/drug effects , Dentate Gyrus/drug effects , Dentate Gyrus/metabolism , Dentate Gyrus/pathology , Disease Models, Animal , Glucose Intolerance/metabolism , Homeostasis , Mice , Microglia/drug effects , Microglia/metabolism , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Signal Transduction/drug effects , Spatial Learning/drug effects
20.
PLoS One ; 10(6): e0127686, 2015.
Article in English | MEDLINE | ID: mdl-26042808

ABSTRACT

Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer's disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4-dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer's disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability of AP-12 to cross the BBB, improve spatial learning and memory in both mice strains, induce anxiolytic action in transgenic mice, and increase expression of hippocampal and cortical proteins (GAD67, Homer-1) related to synaptic plasticity. The compound AP-12 can be seen as a prototype molecule for use in the design of novel drugs useful to halt progression of clinical symptoms (more specifically, anxiety and decline in memory) of neurodegenerative diseases, particularly Alzheimer's disease.


Subject(s)
Amyloid beta-Peptides/genetics , Brain/metabolism , Carrier Proteins/metabolism , Dihydropyridines/pharmacology , Glutamate Decarboxylase/metabolism , Memory/drug effects , Spatial Learning/drug effects , Animals , Anti-Anxiety Agents/pharmacology , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Brain/drug effects , Brain/pathology , Gyrus Cinguli/drug effects , Gyrus Cinguli/metabolism , Gyrus Cinguli/pathology , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Homer Scaffolding Proteins , Humans , Male , Mice, Inbred C57BL , Mice, Transgenic , Time Factors
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