Abeta Plaques Research Articles

Treatment of Alzheimer's Disease and Other Neurodegenerative Conditions by Shifting the Balance from Neurodegeneration to Neural Regeneration

Alzheimer’s disease (AD) is characterized histopathologically by neurodegeneration associated with numerous extracellular Abeta plaques and intraneuronal neurofibrillary tangles of hyperphosphorylated tau. Although studies have implicated both Aβ and tau pathologies in causing cognitive impairment, neurodegeneration, which accounts for the loss of brain mass to the tune of 200-300 g over the average disease progression of 7-10 years, is the most proximal pathology to the development of dementia in AD patients. Substantial evidence suggests that the Aβ and hyperphosphorylated tau (ptau) oligomers, rather than Aβ plaques and tau neurofibrillary tangles (NFTs), are the primary cause of neurodegeneration and dementia.

The multifactorial role of vanillin in amelioration of aluminium chloride and D-galactose induced Alzheimer's disease in mice

The onset and progression of Alzheimer's disease (AD) are influenced by a variety of factors. These include oxidative stress, overexpression of acetylcholinesterase (AChE), depletion of acetylcholine levels, increased beta-secretase mediated conversion of Amyloid Precursor Protein (APP) to Amyloid Beta (Abeta), accumulation of Abeta oligomers, decrease in Brain Derived Neurotrophic factor (BDNF) and accelerated neuronal apoptosis due to elevated levels of caspase-3. The currently available therapeutic approaches are inadequate in affecting these pathological processes except maybe the overexpression of AChE (AChE inhibitors like donepezil, rivastigmine). There is an urgent need to develop disease modifying pharmacotherapeutic interventions which have appreciable safety and cost effectiveness. From previously reported in vitro studies and a preliminary assessment of neuroprotective effect in scopolamine induced dementia-like cognitive impairment in mice, vanillin has been used as the compound of interest in the present study. Vanillin, a phytoconstituent, has been used in humans, safely, in the form of a flavouring agent for various foods, beverages, and cosmetics. Owing to its chemical nature i.e. being a phenolic aldehyde, it has an additional antioxidant property that is congruent to the desirable characteristics that are sought in a suitable novel anti-AD agent. In our study, vanillin proved to have a nootropic effect in healthy Swiss albino mice as well as an ameliorative effect in aluminium chloride and D-galactose induced AD model in mice. Apart from tackling oxidative stress, vanillin was found to reduce the levels of AChE, beta secretase, caspase-3, enhance degradation of Abeta plaques and elevate the levels of BDNF, in cortical and hippocampal regions. Vanillin is a promising candidate for being incorporated into the search for safe and effective anti-AD molecules. However, further research might be needed to warrant its application clinically.

0074 Investigating the Impacts of Pharmacological Slow-Wave Sleep Enhancement on Cognition in an Alzheimer's Disease Model

Abstract Introduction Alzheimer’s disease (AD) is a debilitating and irreversible neurodegenerative disease associated with major disruptions to sleep. Recent works point to a strong bidirectional relationship between loss of slow-wave sleep (SWS), the deepest sleep stage, and the pathological and cognitive features of AD. Here, we investigate the impacts of chronic pharmacological SWS enhancement with gaboxadol, a delta GABAA receptor agonist, on cognitive performance the APP/PS1 mouse model of AD. Currently, we are assessing the impacts of this intervention on Abeta plaque burden. Methods Using electroencephalography (EEG), we first assessed if gaboxadol is capable of stimulating SWS sleep in 6-month-old AD mice. Next, 6-month-old control (CTRL) or AD mice received gaboxadol 5x/week for 4 weeks at the start of the light cycle. Groups underwent subsequent testing in the open field (OF), Y-maze, and contextual fear conditioning (CFC) assays (n = 8-9 mice per group). Data were analyzed using two- or three-way ANOVAs, with repeated measures when appropriate. Results Our EEG studies demonstrate that gaboxadol (6 mg/kg) significantly enhances SWS/NREM from baseline (p < 0.0308). Gaboxadol did not impact gross locomotor behavior assessed by distance travelled in the in the OF. However, rearing was decreased in AD mice compared to CTRL mice (p < 0.0128). In the Y-maze, gaboxadol significantly increased time spent in the novel arm in CTRL (p < 0.0386) but not AD mice. We did not find significant effects of gaboxadol on memory recall in the CFC assay. Conclusion Chronic pharmacological stimulation of SWS using gaboxadol does not show robust cognition-enhancing effects in APP/PS1 mice, but may be cognitively enhancing in CTRL mice. It is possible that longer treatment duration is necessary to rescue cognitive deficits in AD mice. Support (if any) NIA: 5R21AG064774-02 T32 GM7367-46

Amyloid plaque burden and dual tasking impairments on the Timed up and go test in Parkinson disease (P5-11.006)

<h3>Objective:</h3> Dual tasking (DT) impairments in Parkinson disease (PD) are a correlate of fall risk. Their biological basis may reflect multiple underlying pathological causes. <h3>Background:</h3> Low-level amyloid-beta (Abeta) plaque burden is known to correlate with gait and cognitive impairments in PD. It is possible that Abeta plaque burden may exacerbate fall risk by worsening dual tasking cost, though this has not been evaluated to date. <h3>Design/Methods:</h3> In a cross-sectional cohort of 20 participants with PD, we explored the association between Abeta plaque burden and dual task cost (DTC) on the timed up and go test (TUG). TUG gait parameters were assessed using Ambulatory Parkinson’s disease monitoring (APDM) OPAL wearable sensors. Baseline TUG testing was followed by TUG testing during which the participant performed a cognitive task. DTC was calculated as the percentage difference in seconds between the two tasks. Regional Abeta plaque burden was assessed by [11C]Pittsburgh compound B (PiB) positron emission tomography (PET) imaging. Bivariate Pearson’s r statistic was calculated between DTC and PiB distribution volume ratio (DVR) in different regions of interest. <h3>Results:</h3> DTC during the TUG show no significant correlations with PiB DVR in the total cortical mantle (r=0.061, p=0.797), visuospatial cortex (r=0.061, p=0.798), striatum (r=0.033, p=0.890), or thalamus (r=0.041, p=0.865) but did correlate with elevated PiB DVR in the substantia nigra (r=0.535, p=0.015). <h3>Conclusions:</h3> DTC in PD does not correlate with supratentorial amyloid plaque burden but may reflect mixed neurodegenerative pathology, including Abeta plaque burden, in the substantia nigra. <b>Disclosure:</b> Ms. Harrie has nothing to disclose. The institution of Dr. Hampstead has received research support from NIH. The institution of Dr. Hampstead has received research support from Department of Veterans Affairs. Dr. Hampstead has received intellectual property interests from a discovery or technology relating to health care. Dr. Hampstead has received publishing royalties from a publication relating to health care. Catherine Lewis has nothing to disclose. Ms. Herreshoff has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Huxley Medical Inc. Dr. Kotagal has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Movement Disorders Society. The institution of Dr. Kotagal has received research support from NIH. The institution of Dr. Kotagal has received research support from VA Healthcare System.

Elevation of membralin can improve the cognitive decline in 5xFAD mice

AbstractBackgroundAlzheimer’s Disease (AD) is the most prominent neurodegenerative dementia in the aging human population, with pathological hallmarks that include deposition of extracellular β‐amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Aging is one of the largest risk factors for developing AD. Disturbed protein homeostasis is associated with the aging process. However, the cell‐type‐specific contribution of disturbed protein homeostasis to the aging process and AD progression is unclear. Our previous works identified a novel Endoplasmic‐Reticulum‐Associated Degradation (ERAD) component, membralin/TMEM259, which can mediate the turnover of nicastrin protein, consequently affect gamma‐secretase complex formation and activity. Knockdown membralin in an AD mouse model (TgCRND8) exaggerated beta‐amyloid‐associated neuronal damage. Moreover, selective deletion of membralin in astrocytes decreased excitatory amino acid transporter 2 (EAAT2) expression and induced neuroinflammation. Therefore, we hypothesized that elevation of membralin would improve beta‐amyloid‐associated cognitive decline and alleviate neuroinflammation.MethodTo investigate this, we generated a transgenic mouse line carrying the membralin gene, which expression was driven by a Prion promoter, and crossed this mouse line with 5XFAD mice. We performed behavioral studies using the Barnes Maze, Morris Water Maze, and Fear Conditioning tests on the 6‐month‐old animals. Biochemical and pathological analyses were used to determine the load of beta‐amyloid accumulation and neuroinflammation phenotype.ResultElevation of membralin improved spatial learning and memory in 5xFAD mice. Abeta 42 and Abeta 40 levels significantly reversely correlated with the membralin protein level. The abeta plaques appeared to be compact, and there were more microglia associated with the abeta plaques in the membralin transgenic animals crossed with the 5xFAD animals.ConclusionOverall, this suggests that elevation of membralin improves beta‐amyloid‐associated cognitive decline. And this could be partially from the effects of membralin in regulating neuroinflammation. Modulation of glial ER homeostasis could be a promising target to regulate neuroinflammation for AD therapy.

Optimized ACI‐24, an amyloid beta (Abeta) vaccine that safely drives immunity to oligomers and Pyroglutamate Abeta, key pathological species of Alzheimer’s disease (AD)

AbstractBackgroundAmyloid immunotherapy has received recent clinical validation with monoclonal antibodies. Vaccines, such as optimized ACI‐24, are designed to produce a broader, robust antibody response against multiple pathologic forms of Abeta with the added advantage to reduce treatment frequency. Optimized ACI‐24 builds on the initial safety, immunogenicity and pharmacodynamic data of ACI‐24 that has been studied in AD and Down Syndrome‐related AD. Optimized ACI‐24 is formulated with the additional immune cell help via a non‐Abeta, universal T‐helper cell peptide, aiming to insure sustained antibody production, particularly against pathological Abeta species, such as oligomers and truncated pyroglutamate.MethodOptimized ACI‐24 was generated using the SupraAntigen® platform. Mice and non‐human primates were immunized and sera/plasma obtained to measure titers against Abeta1‐42, pyroglutamate (Abeta3‐42) and oligomers. Epitope mapping, immunohistochemistry on different human tissues, including AD brains were performed.ResultImmunization of mice and cynomolgus monkeys with optimized ACI‐24 resulted in potent antigen specific IgG levels. The polyclonal antibody response was observed to mature over time with higher affinity IgGs emerging as well as an increase in titers of IgGs that recognized the highly neurotoxic Abeta species including truncated pyroglutamate and pathological Abeta oligomers. Epitope mapping confirmed the induction of a broader spectrum of antibodies recognizing the N‐terminal containing and the truncated species of pathological Abeta, as compared to the previously clinically tested Abeta vaccines. In addition, target engagement was demonstrated as the immunized monkey sera labeled Abeta plaques in AD patient brain sections while did not show any binding to other human tissues.ConclusionThese preclinical data illustrate that optimized ACI‐24 generates IgGs with a broader N‐terminal Abeta sequence recognition than offered by clinically tested mAbs or Abeta vaccines. This unique binding profile for the pathogenic forms of Abeta, including truncated pyroglutamate and toxic oligomers, is encouraging as it combines the targets of mAbs, such as Aducanumab and Donanemab, recently linked to clinical benefits, and thus, the potential of enhancing plaque reduction. The presented data support the fast progression of optimized ACI‐24 into clinical development as a disease modifying treatment with potential for prevention in AD and Down Syndrome‐related AD.

Novel HDAC11 Inhibitors for Alzheimer’s Disease Treatment in Preclinical Models

AbstractBackgroundHDAC activity and expression are implicated in cognitive function and animal research in Alzheimer’s disease (AD). This strongly suggests that HDAC inhibition is a promising lead toward developing improved treatment for cognitive decline. However, little is known about the role of HDAC11 in the etiopathogenesis of AD and whether HDAC11 can be a potential therapeutic target for AD, mainly due to lack of knowledge of HDAC11 in AD and absence of brain penetrant HDAC11 inhibitors.MethodWe synthesized and analyzed novel HDAC11‐selective and brain penetrant inhibitors and performed treatment using our novel HDAC11 inhibitors in the 5xFAD mice. The treatment outcomes are measured by PET imaging for target engagement, live animal optical imaging for amyloid neuropathology and behavioral tests for cognitive functions.ResultHerein we report the development and characterization of PB94, a novel HDAC11 inhibitor. It exhibited potency and selectivity against HDAC11 with IC50 = 108 nM and &gt;39‐fold selectivity over other HDAC isoforms, respectively. Pharmacokinetic/pharmacodynamic evaluation indicated PB94 possesses promising drug‐like properties. An array of in vitro assays was conducted to predict the safety, efficacy, and function of PB94. Additionally, PB94 was radiolabeled with carbon‐11 as [11C]PB94 for positron emission tomography (PET), which revealed significant brain uptake and metabolic properties suitable for DRUG DEVELOPMENT in live animals. Furthermore, we demonstrated that pharmacological inhibition of HDAC11 by PB94 can reduce abeta plaques and neuroinflammation by neuroimaging, in association with improved cognition in these animals.ConclusionOur findings show that HDAC11 may be a potential target for AD DRUG DEVELOPMENT. Our results set the stage for further development of PB94 as a potential therapeutic agent against AD.

Regional correlation of biochemical measures of amyloid and tau phosphorylation in the brain

Alzheimer’s disease (AD) neuropathologic change is characterized by amyloid plaques and neurofibrillary tangles (NFTs) that consist of aggregated amyloid beta (Abeta) and hyperphosphorylated tau proteins (p-tau), respectively. Although the global relationship between Abeta and p-tau has been studied for decades, it is still unclear whether a regional correlation exists between Abeta and p-tau in the human brain. Recent studies in cerebrospinal fluid (CSF) have suggested that tau phosphorylation at specific sites such as T217 is modified at an early stage of AD when amyloid plaques become detectable. We applied biochemical and mass spectrometry methods in human brain samples with and without Abeta plaque pathology to measure site-specific phosphorylation occupancies in soluble and insoluble tau. Our quantitative results identified multiple residues specifically hyper-phosphorylated in AD, including at sites T111, T153, S184 (or S185), T205, S208, T217, S262, and S285 in brain soluble tau. In contrast, the most enriched phosphorylated residues in brain insoluble tau were T111, S113, T153, T181, S199, S202, T205, T217, T231, S262, and S396. Tau phosphorylation occupancies in the insoluble fraction were relatively constant across brain regions, suggesting that tau has a consistent phosphorylation pattern once it has aggregated into NFTs. We did not find regional association between Abeta42 and insoluble tau. However, the phosphorylation profile of soluble tau in AD brain was highly correlated to that in AD CSF, which was analyzed in a previous study. We also found a higher regional association between total Abeta42 and soluble tau phosphorylation occupancy at residues T111, T153 and T217 in the brain. This study provides insights into regional interactions between amyloidosis and specific tau phosphorylated residues in the human brain and may explain the specific increases of tau species phosphorylation observed in AD CSF.

Discovery of 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c’]dipyridine ([18F]PI-2014) as PET tracer for the detection of pathological aggregated tau in Alzheimer’s disease and other tauopathies

The compound screening was initiated with a direct staining assay to identify compounds binding to Tau aggregates and not Abeta plaques using human brain sections derived from late stage Alzheimer’s disease donors. The binding of Tau aggregate selective compounds was then quantitatively assessed with human brain derived paired helical filaments utilizing the label-free Back Scattering Interferometry assay. In vivo biodistribution experiments of selected fluorine-18 labeled compounds were performed in mice to assess brain uptake, brain washout, and defluorination. Compound 11 emerged as the most promising candidate, displaying high in vitro binding affinity and selectivity to neurofibrillary tangles. Fluorine-18 labeled compound 11 showed high brain uptake and rapid washout from the mouse brain with no observed bone uptake. Furthermore, compound 11 was able to detect Tau aggregates in tauopathy brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick’s disease donors. Thus, 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c’]dipyridine (PI-2014, compound 11) was selected for characterization in a first-in-human study.

Taurodeoxycholate, a master key locking both priming and activation signal necessary for inflammasomal activation of microglia by Amyloid beta in Alzheimer’s diseases

Abstract Alzheimer’s disease (AD) is an inflammatory neurodegenerative condition characterized by deposition of amyloid beta (Abeta) in the brain and origins dementia. Neuronal apoptosis following neuroinflammation by Abeta impairs cognition and memory. In this study we focused on Taurodeoxyxcholate (TDCA) is an active bile acid derivative with potent anti-inflammatory function. In 5× Familial Alzheimer’s disease (5xFAD) mice model, chronic administration of TDCA in 5xFAD mice improved learning and memory in different memory test compared with PBS group. TDCA treatment significantly decreased neuronal apoptosis, load of Abeta plaques, the number of activated GFAP+ astrocytes and Iba-1+ microglia in different brain region of 5xFAD mice. CD11bhiGr1intF4/80+ myeloid cells in brain and spleen increased significantly in TDCA-treated group compared to PBS-treated group when brain single cell were immune-stained. In vitro, TDCA increased phagocytosis of Abeta. TDCA suppressed NLRP3-ASC oligomerization and production of mature IL-1β/IL-18 in Microglia by Abeta. TDCA inhibited Ca++ influx incurred by ATP or BzATP (P2X7 agonists). Compared with wild type, Ca++ influx of macrophages from TGR5 KO mice was like that of P2X7 KO mice in response to BzATP, suggesting that TDCA might play role as an inverse agonist for TGR5 complexed with P2X7. TDCA activates adenylate cyclase and cAMP inhibit priming phase of inflammasomal activation and oligomerization of NLRP3-ASC complex, suggesting that TDCA suppresses both priming and activation phase of NLRP3 inflammasome. TDCA and its novel chemical derivatives could be better choice in ameliorating broad spectrum of neuroinflammation to improve cognition and memory in AD patients.

SCIDOT-39. K16ApoE ENHANCES Aβ-ASSOCIATED 11C-PiB DEPOSITION AND PET SIGNAL IN APP/PS1 TRANSGENIC MICE

Abstract OBJECTIVE The K16ApoE peptide enhances delivery of multiple agents across the blood-brain barrier (BBB). Transgenic mouse models are central to elucidating the underlying pathophysiology of Alzheimer’s Disease (AD) and provide a system for evaluating novel therapeutic strategies. PET imaging plays a central clinical role in diagnosing human cases of AD but has had variable performance in mouse models. We investigated the role of K16ApoE to enhance delivery of a radiolabeled PET imaging tracer, 11C-PiB and assess whether this corresponds to improved PET sensitivity in APP/PS1 transgenic mice. METHODS Brain-delivery of 11C-PiB was accomplished by successive injections of K16ApoE and 11C-PiB. Distribution of 11C-PiB to the brain and heart was quantified via dynamic PET/CT imaging and digital autoradiography. RESULTS K16ApoE increased the brain uptake of 11C-PiB in both wild-type (WT) and APP/PS1 mice. Administration of K16ApoE increased the PET standard uptake value of 11C-PiB at 5 minutes in WT mice from 1.132 to 2.963 (p=0.006) and in APP/PS1 mice from 0.842 to 3.268 (p=0.016). Enhancement peaked at 5 minutes. Binding was reversible with similarly increased kinetics in both WT and APP/PS1 mice. The absolute values were higher in APP/PS1 mice suggesting increased retention. The increased retention in APP/PS1 mice was consistent with specific binding to A-beta plaques as unlabeled PiB reduced 11C-PiB signal retention. CONCLUSION K16ApoE mediates enhancement of 11C-PiB signal in APP/PS1 mice brains with increased PET sensitivity. There is increased uptake kinetics in both WT and APP/PS1 mice with specific A-beta plaque binding in the latter. This enhanced delivery of the PET tracer has implications for development and testing of new hypotheses and the efficacy of novel therapeutic paradigms. K16ApoE has potential for improving delivery of several agents across the BBB. This has implication for delivery of diagnostic and therapeutic agents for neurodegenerative and neuro-oncologic diseases.

Endogenous mouse huntingtin is highly abundant in cranial nerve nuclei, co-aggregates to Abeta plaques and is induced in reactive astrocytes in a transgenic mouse model of Alzheimer\u2019s disease

Pathogenic variants of the huntingtin (HTT) protein and their aggregation have been investigated in great detail in brains of Huntington’s disease patients and HTT-transgenic animals. However, little is known about the physiological brain region- and cell type-specific HTT expression pattern in wild type mice and a potential recruitment of endogenous HTT to other pathogenic protein aggregates such as amyloid plaques in cross seeding events. Employing a monoclonal anti-HTT antibody directed against the HTT mid-region and using brain tissue of three different mouse strains, we detected prominent immunoreactivity in a number of brain areas, particularly in cholinergic cranial nerve nuclei, while ubiquitous neuronal staining appeared faint. The region-specific distribution of endogenous HTT was found to be comparable in wild type rat and hamster brain. In human amyloid precursor protein transgenic Tg2576 mice with amyloid plaque pathology, similar neuronal HTT expression patterns and a distinct association of HTT with Abeta plaques were revealed by immunohistochemical double labelling. Additionally, the localization of HTT in reactive astrocytes was demonstrated for the first time in a transgenic Alzheimer’s disease animal model. Both, plaque association of HTT and occurrence in astrocytes appeared to be age-dependent. Astrocytic HTT gene and protein expression was confirmed in primary cultures by RT-qPCR and by immunocytochemistry. We provide the first detailed analysis of physiological HTT expression in rodent brain and, under pathological conditions, demonstrate HTT aggregation in proximity to Abeta plaques and Abeta-induced astrocytic expression of endogenous HTT in Tg2576 mice.

Cell Type-Specific Human APP Transgene Expression by Hippocampal Interneurons in the Tg2576 Mouse Model of Alzheimer's Disease.

Amyloid precursor protein (APP) transgenic animal models of Alzheimer’s disease have become versatile tools for basic and translational research. However, there is great heterogeneity of histological, biochemical, and functional data between transgenic mouse lines, which might be due to different transgene expression patterns. Here, the expression of human APP (hAPP) by GABAergic hippocampal interneurons immunoreactive for the calcium binding proteins parvalbumin, calbindin, calretinin, and for the peptide hormone somatostatin was analyzed in Tg2576 mice by double immunofluorescent microscopy. Overall, there was no GABAergic interneuron subpopulation that did not express the transgene. On the other hand, in no case all neurons of such a subpopulation expressed hAPP. In dentate gyrus molecular layer and in stratum lacunosum moleculare less than 10% of hAPP-positive interneurons co-express any of these interneuron markers, whereas in stratum oriens hAPP-expressing neurons frequently co-express these interneuron markers to different proportions. We conclude that these neurons differentially contribute to deficits in young Tg2576 mice before the onset of Abeta plaque pathology. The detailed analysis of distinct brain region and neuron type-specific APP transgene expression patterns is indispensable to understand particular pathological features and mouse line-specific differences in neuronal and systemic functions.

Isoflurane anesthesia promotes cognitive impairment by inducing expression of β-amyloid protein-related factors in the hippocampus of aged rats.

Isoflurane anesthesia has been shown to be responsible for cognitive impairment in Alzheimer’s disease (AD) and development of AD in the older age groups. However, the pathogenesis of AD-related cognitive impairments induced by isoflurane anesthesia remains elusive. Thus, this study was designed to investigate the mechanism by which isoflurane anesthesia caused AD-related cognitive impairments. Aged Wistar rats were randomly divided into 6 groups (n = 12), 1 control group (CONT) and 5 isoflurane treated (ISO) groups (ISO 0, ISO 0.5D, ISO 1D, ISO 3D and ISO 7D). The CONT group inhaled 30% O2 for 2 h without any anesthesia. ISO groups were placed under anesthesia with 3% isoflurane and then exposed to 1.5% isoflurane delivered in 30% O2 for 2 h. Rats in each ISO group were then analyzed immediately (ISO 0) or at various time points (0.5, 1, 3 or 7 day) after this exposure. Cognitive function was assessed using the Morris water maze test. Protein levels of amyloid precursor protein (APP), β-site APP cleavage enzyme-1 (BACE-1) and Aβ42 peptide were analyzed in hippocampal samples by Western blot. β-Amyloid (Abeta) plaques were detected in hippocampal sections by Congo red staining. Compared with controls, all ISO groups showed increased escape latency and impaired spatial memory. Isoflurane increased APP mRNA expression and APP protein depletion, promoting Aβ42 overproduction, oligomerization and accumulation. However, isoflurane did not affect BACE-1 expression. Abeta plaques were observed only in those ISO groups sacrificed at 3 or 7 d. Our data indicate that aged rats exposed to isoflurane had increased APP mRNA expression and APP protein depletion, with Aβ42 peptide overproduction and oligomerization, resulting in formation of Abeta plaques in the hippocampus. Such effects might have contributed to cognitive impairments, including in spatial memory, observed in these rats after isoflurane anesthesia.

Hyperexpression of STIM2 protein lowers the amount of Abeta plaques in the brain of Alzheimer's disease mouse model

The role of the STIM2→nSOCE signaling pathway was investigated in a model of Alzheimer's disease (AD) 5FAD mice that express amyloid and presenilin toxicity simultaneously. It was observed that expression of STIM2 protein was downregulated in the hippocampus of adult 5FAD mice at the age of 4 and 6 months. It was shown that expression of PSD95 protein was downregulated together with STIM2 protein. It was established that hyperexpression of STIM2 protein in the hippocampus of adult mice lowered the amount of amyloid plaques in the cortex of 5FAD mice by three times. The observed data confirms the scientific hypothesis that activation of STIM2-dependent store-operated calcium entry can have a therapeutic effect for treatment in AD.

Ablation of CCAAT/Enhancer-Binding Protein Delta (C/EBPD): Increased Plaque Burden in a Murine Alzheimer's Disease Model.

Alzheimer’s disease (AD) and prion diseases carry a significant inflammatory component. The astrocytic overexpression of CCAAT/enhancer-binding protein delta (C/EBPD) in prion- and AD-affected brain tissue prompted us to study the role of this transcription factor in murine model systems of these diseases. Ablation of C/EBPD had neither in the AD model (APP/PS1double transgenic mice) nor in the prion model (scrapie-infected C57BL/6 mice) an influence on overt clinical symptoms. Moreover, the absence of C/EBPD did not affect the extent of the disease-related gliosis. However, C/EBPD-deficient APP/PS1 double transgenic mice displayed significantly increased amyloid beta (Abeta) plaque burdens while amyloid precursor protein (APP) expression and expression of genes involved in beta amyloid transport and turnover remained unchanged. Gene expression analysis in mixed glia cultures demonstrated a strong dependency of complement component C3 on the presence of C/EBPD. Accordingly, C3 mRNA levels were significantly lower in brain tissue of C/EBPD-deficient mice. Vice versa, C3 expression in U-373 MG cells increased upon transfection with a C/EBPD expression vector. Taken together, our data indicate that a C/EBPD-deficiency leads to increased Abeta plaque burden in AD model mice. Furthermore, as shown in vivo and in vitro, C/EBPD is an important driver of the expression of acute phase response genes like C3 in the amyloid-affected CNS.

Disruption of amyloid plaques integrity affects the soluble oligomers content from Alzheimer disease brains.

The implication of soluble Abeta in the Alzheimer’s disease (AD) pathology is currently accepted. In fact, the content of soluble extracellular Abeta species, such as monomeric and/or oligomeric Abeta, seems to correlate with the clinico-pathological dysfunction observed in AD patients. However, the nature (monomeric, dimeric or other oligomers), the relative abundance, and the origin (extra-/intraneuronal or plaque-associated), of these soluble species are actually under debate. In this work we have characterized the soluble (defined as soluble in Tris-buffered saline after ultracentrifugation) Abeta, obtained from hippocampal samples of Braak II, Braak III–IV and Braak V–VI patients. Although the content of both Abeta40 and Abeta42 peptides displayed significant increase with pathology progression, our results demonstrated the presence of low, pg/µg protein, amount of both peptides. This low content could explain the absence (or below detection limits) of soluble Abeta peptides detected by western blots or by immunoprecipitation-western blot analysis. These data were in clear contrast to those published recently by different groups. Aiming to explain the reasons that determine these substantial differences, we also investigated whether the initial homogenization could mobilize Abeta from plaques, using 12-month-old PS1xAPP cortical samples. Our data demonstrated that manual homogenization (using Dounce) preserved the integrity of Abeta plaques whereas strong homogenization procedures (such as sonication) produced a vast redistribution of the Abeta species in all soluble and insoluble fractions. This artifact could explain the dissimilar and somehow controversial data between different groups analyzing human AD samples.

Self-assembling nanofibers alter the processing of amyloid precursor protein in a transgenic mouse model of Alzheimer’s disease

Background:Alzheimer’s disease (AD) is one of the most common dementia, which is not effectively cured to date. Amyloid-beta (Abeta) deposition cascade and disintegrity of brain extracellular matrix (ECM) scaffold attribute to the progress of AD. Thus, it maybe an effective way to treat AD by altering the processing of amyloid precursor protein (APP) and regaining the integrity of ECM. The peptide amphiphile (PA) with a laminin epitope isoleucine–lysine–valine–alanine–valine (IKVAV) (IKVAV-PA) can be trigged into ECM in vivo. In addition, IKVAV-PA could significantly improve cognitive impairment with remarkable increase of endoneurogensis in the hippocampus, as well as reduction of burden of amyloid plaque in the brain.Methods:We used heterozygous AbetaPPswe/PS1dE9 double transgenic mice as the animal model of AD. After 1 week of initial stereotaxic administration into bilateral hippocampus, the mice were subjected to the Morris Water Maze (MWM) test. At the end of MWM test, immunohistochemical staining, Western blot and real-time polymerase chain reaction (PCR) were performed in mice.Results:Here we showed that IKVAV-PA significantly improved cognitive impairment accompanying with reducing the burden of Abeta plaques, as well as the levels of soluble Abeta1-40 and Abeta1-42 in the cortex and hippocampus after 2 weeks of initial administration into bilateral hippocampus. Further examination demonstrated that IKVAV-PA also altered the processing of APP via inhibiting the gene expression of beta-secretase (BACE1), as well as improving the gene expression of insulin-degrading enzyme (IDE) and neprilysin (NEP).Conclusion:Our data suggest that IKVAV-PA may serve as an alternative therapeutic intervention for treating the learning and memory losses in AD.

ADULT MESENCHYMAL STEM CELLS HAVE A POTENTIAL TO LOWER CEREBRAL ABETA AMYLOIDOSIS IN AN ALZHEIMER'S DISEASE MOUSE MODEL

Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by extracellular senile plaques, primarily composed of polymerized amyloid-beta (Abeta) peptides. There is currently no cure for this devastating disease that represents one of today's major healthcare challenges due to its severe socio-economic burden. The huge potential offered by human adult stem cells for the treatment of various neurodegenerative disorders is supported by a number of ongoing clinical trials, however the impact of these cells on Abeta amyloid pathology has not been yet investigated in a pre-clinical study. We evaluated the impact of a repeated intravenous delivery of clinical grade human ischemic tolerant adult mesenchymal stem cells (itMSC) on Abeta amyloid pathology in a mouse model of AD. Ten weeks of itMSC treatment safely reduced cerebral Abeta plaques in aged amyloid-depositing Alzheimeric mice (- ∼ 30 %, p< 0.0001). Plaque-associated microglia significantly increased in density, suggesting that these cells contributed to plaque removal following itMSC treatment. The impact of itMSC delivery on recovering brain dysfunction in Alzheimeric mice is currently being investigated using in vivo functional neuroimaging. Our pre-clinical results indicate that adult itMSC can decrease Abeta amyloid pathology in a mouse model of AD. As revealed in the current pre-clinical study, the combination of safety and efficacy to remove amyloid plaques offered by itMSC, together with successfully completed safety phase I clinical trials, may put itMSC as a perspective candidate for treating Abeta amyloid pathology in AD.

Two Alzheimer's Immunotherapy Drugs Fail in Four Studies

Two Alzheimer's Immunotherapy Drugs Fail in Four Studies