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Neuroscience Jan 2024The main clinical manifestation of Alzheimer's disease is progressive cognitive decline, and its pathological features are β-amyloid (Aβ) deposition, neurofibrillary...
ApoE Mimic Peptide COG1410 Reduces Aβ Deposition and Improves Cognitive Function by Inducing the Transformation of A1/A2 Reactive Astrocytes and Increasing the BDNF Concentration in Brain of APP/PS1 Double Transgenic Mice.
The main clinical manifestation of Alzheimer's disease is progressive cognitive decline, and its pathological features are β-amyloid (Aβ) deposition, neurofibrillary tangles, synaptic dysfunction and neuron death. Neuroinflammation is an important reason for the occurrence and development of AD, which is mainly manifested by the accumulation of activated microglia and reactive astrocytes. Apolipoprotein E (ApoE) is one of the most important apolipoprotein in the brain, which is related to metabolism, aggregation and toxicity of Aβ. However, the underlying mechanism needs to be further explored. In this study, we studied the effect of ApoE mimetic peptide COG1410 on spatial learning and memory functions, deposition of Aβ in the dentate gyrus (DG) of APP/PS1 transgenic mice, and the different effects of A1 and A2 subtypes of reactive astrocytes. Administration of COG1410 effectively improved performance in spatial learning and memory of APP/PS1 mice, reduced Aβ deposition and significantly reverted the ratio of A1/A2 reactive astrocytes, which could be associated with BDNF/TrkB signaling pathway. On the whole, the present findings suggest new possibility of using apolipoprotein E mimetic peptide to treat AD with potential effectiveness.
Topics: Mice; Animals; Mice, Transgenic; Brain-Derived Neurotrophic Factor; Astrocytes; Brain; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Cognition; Amyloid beta-Protein Precursor; Disease Models, Animal; Presenilin-1
PubMed: 38006963
DOI: 10.1016/j.neuroscience.2023.11.023 -
Research Square Nov 2023The recently discovered interaction between presenilin 1 (PS1), a catalytic subunit of γ-secretase responsible for the generation of amyloid-β(Aβ) peptides, and...
The recently discovered interaction between presenilin 1 (PS1), a catalytic subunit of γ-secretase responsible for the generation of amyloid-β(Aβ) peptides, and GLT-1, the major glutamate transporter in the brain (EAAT2 in the human) may provide a mechanistic link between two important pathological aspects of Alzheimer's disease (AD): abnormal Aβoccurrence and neuronal network hyperactivity. In the current study, we employed a FRET-based approach, fluorescence lifetime imaging microscopy (FLIM), to characterize the PS1/GLT-1 interaction in its native environment in the brain tissue of sporadic AD (sAD) patients. There was significantly less interaction between PS1 and GLT-1 in sAD brains, compared to tissue from patients with frontotemporal lobar degeneration (FTLD), or non-demented age-matched controls. Since PS1 has been shown to adopt pathogenic "closed" conformation in sAD but not in FTLD, we assessed the impact of changes in PS1 conformation on the interaction. Familial AD (fAD) PS1 mutations which induce a "closed" PS1 conformation similar to that in sAD brain and gamma-secretase modulators (GSMs) which induce a "relaxed" conformation, reduced and increased the interaction, respectively. This indicates that PS1 conformation seems to have a direct effect on the interaction with GLT-1. Furthermore, using biotinylation/streptavidin pull-down, western blotting, and cycloheximide chase assays, we determined that the presence of PS1 increased GLT-1 cell surface expression and GLT-1 homomultimer formation, but did not impact GLT-1 protein stability. Together, the current findings suggest that the newly described PS1/GLT-1 interaction endows PS1 with chaperone activity, modulating GLT-1 transport to the cell surface and stabilizing the dimeric-trimeric states of the protein. The diminished PS1/GLT-1 interaction suggests that these functions of the interaction may not work properly in AD.
PubMed: 37986905
DOI: 10.21203/rs.3.rs-3495211/v1 -
Journal of Alzheimer's Disease : JAD 2023Exposure to stress early in life increases the susceptibility to Alzheimer's disease (AD) pathology in aged AD mouse models. So far, the underlying mechanisms have...
BACKGROUND
Exposure to stress early in life increases the susceptibility to Alzheimer's disease (AD) pathology in aged AD mouse models. So far, the underlying mechanisms have remained elusive.
OBJECTIVE
To investigate 1) effects of early life stress (ELS) on early functional signs that precede the advanced neuropathological changes, and 2) correlate synaptosomal protein content with cognition to identify neural correlates of AD.
METHODS
APPswe/PS1dE9 mice and littermates were subjected to ELS by housing dams and pups with limited bedding and nesting material from postnatal days 2-9. At 3 months of age, an age where no cognitive loss or amyloid-β (Aβ) pathology is typically reported in this model, we assessed hippocampal Aβ pathology, synaptic strength and synapse composition and interneuron populations. Moreover, cognitive flexibility was assessed and correlated with synaptosomal protein content.
RESULTS
While ELS did not affect Aβ pathology, it increased synaptic strength and decreased the number of calretinin+ interneurons in the hippocampal dentate gyrus. Both genotype and condition further affected the level of postsynaptic glutamatergic protein content. Finally, APP/PS1 mice were significantly impaired in cognitive flexibility at 3 months of age, and ELS exacerbated this impairment, but only at relatively high learning criteria.
CONCLUSIONS
ELS reduced cognitive flexibility in young APP/PS1 mice and altered markers for synapse and network function. These findings at an early disease stage provide novel insights in AD etiology and in how ELS could increase AD susceptibility.
Topics: Animals; Male; Mice; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Cognitive Dysfunction; Disease Models, Animal; Interneurons; Mice, Transgenic; Plaque, Amyloid; Presenilin-1; Synapses; Stress, Physiological
PubMed: 37980670
DOI: 10.3233/JAD-230727 -
Journal of Neuroinflammation Nov 2023Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic...
Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin with antioxidant, anti-inflammatory, and antitumor properties. However, as the effects of C3G on the amyloidogenic pathway, autophagy, tau phosphorylation, neuronal cell death, and synaptic plasticity in Alzheimer's disease models have not been reported, we attempted to investigate the same in the brains of APPswe/PS1ΔE9 mice were analyzed. After oral administration of C3G (30 mg/kg/day) for 16 weeks, the cortical and hippocampal regions in the brains of APPswe/PS1ΔE9 mice were analyzed. C3G treatment reduced the levels of soluble and insoluble Aβ (Aβ40 and Aβ42) peptides and reduced the protein expression of the amyloid precursor protein, presenilin-1, and β-secretase in the cortical and hippocampal regions. And C3G treatment upregulated the expression of autophagy-related markers, LC3B-II, LAMP-1, TFEB, and PPAR-α and downregulated that of SQSTM1/p62, improving the autophagy of Aβ plaques and neurofibrillary tangles. In addition, C3G increased the protein expression of phosphorylated-AMPK/AMPK and Sirtuin 1 and decreased that of mitogen-activated protein kinases, such as phosphorylated-Akt/Akt and phosphorylated-ERK/ERK, thus demonstrating its neuroprotective effects. Furthermore, C3G regulated the PI3K/Akt/GSK3β signaling by upregulating phosphorylated-Akt/Akt and phosphorylated-GSK3β/GSK3β expression. C3G administration mitigated tau phosphorylation and improved synaptic function and plasticity by upregulating the expression of synapse-associated proteins synaptophysin and postsynaptic density protein-95. Although the potential of C3G in the APPswe/PS1ΔE9 mouse models has not yet been reported, oral administration of the C3G is shown to protect the brain and improve cognitive behavior.
Topics: Mice; Animals; Mice, Transgenic; Anthocyanins; Glycogen Synthase Kinase 3 beta; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; AMP-Activated Protein Kinases; Alzheimer Disease; Cognition; Brain; Glucosides; Amyloid beta-Peptides
PubMed: 37978414
DOI: 10.1186/s12974-023-02950-3 -
Molecular Cell Nov 2023γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate...
γ-Secretases mediate the regulated intramembrane proteolysis (RIP) of more than 150 integral membrane proteins. We developed an unbiased γ-secretase substrate identification (G-SECSI) method to study to what extent these proteins are processed in parallel. We demonstrate here parallel processing of at least 85 membrane proteins in human microglia in steady-state cell culture conditions. Pharmacological inhibition of γ-secretase caused substantial changes of human microglial transcriptomes, including the expression of genes related to the disease-associated microglia (DAM) response described in Alzheimer disease (AD). While the overall effects of γ-secretase deficiency on transcriptomic cell states remained limited in control conditions, exposure of mouse microglia to AD-inducing amyloid plaques strongly blocked their capacity to mount this putatively protective DAM cell state. We conclude that γ-secretase serves as a critical signaling hub integrating the effects of multiple extracellular stimuli into the overall transcriptome of the cell.
Topics: Mice; Animals; Humans; Amyloid Precursor Protein Secretases; Proteome; Signal Transduction; Membrane Proteins; Alzheimer Disease
PubMed: 37977120
DOI: 10.1016/j.molcel.2023.10.029 -
MedRxiv : the Preprint Server For... Mar 2024Prior studies using the ADSP data examined variants within presenilin-2 ( ), presenilin-1 ( ), and amyloid precursor protein ( ) genes. However, previously-reported...
BACKGROUND
Prior studies using the ADSP data examined variants within presenilin-2 ( ), presenilin-1 ( ), and amyloid precursor protein ( ) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer's Disease Sequencing Project (ADSP).
OBJECTIVE
To characterize previously-reported clinically-relevant variants and DM variants in within the participants from the ADSP.
METHODS
We identified rare variants (MAF <1%) previously-reported in , and in the available ADSP sample of 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available for research-use (N = 31,490). We additionally curated variants in these three genes from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes.
RESULTS
We detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in , 25 in , and 2 in . The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with non-carriers (p-value=7.8×10 ).
CONCLUSION
A small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to non-carriers.
PubMed: 37961373
DOI: 10.1101/2023.10.24.23297227 -
BioRxiv : the Preprint Server For... Nov 2023Interictal spikes (IIS) and seizures are well-documented in Alzheimer's disease (AD). IIS typically outnumber seizures, supporting their role as a prominent EEG...
UNLABELLED
Interictal spikes (IIS) and seizures are well-documented in Alzheimer's disease (AD). IIS typically outnumber seizures, supporting their role as a prominent EEG biomarker in AD. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) also occur, but it is currently unknown how HFOs compare to IIS. Therefore, we asked whether the incidence of HFOs and IIS differed and if they are differentially affected by behavioral state. We used three mouse lines that simulate aspects of AD: Tg2576, presenilin 2 knockout, and Ts65Dn mice. We recorded and quantified HFOs and IIS in the hippocampus during wakefulness, slow-wave sleep, and rapid eye movement sleep. In all three mouse lines, HFOs were more frequent than IIS. High numbers of HFOs correlated with fewer IIS, suggesting for the first time possible competing dynamics among them in AD. Notably, HFOs occurred in more behavioral states than IIS. In summary, HFOs were the most abundant EEG abnormality when compared to IIS, and occurred in all behavioral states, suggesting they are a better biomarker than IIS. These findings pertained to three mouse lines, which is important because they simulate different aspects of AD. We also show that HFOs may inhibit IIS.
SHORT SUMMARY
Interictal spikes (IIS) and seizures are common in Alzheimer's disease (AD). IIS are more frequent than seizures and occur during earlier disease stages. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) occur, but a comparison between IIS and HFOs is lacking. Here we used 3 mouse lines with AD features and local field potential recordings to quantify IIS and HFOs. We found that HFOs outnumbered IIS and that their total numbers were inversely correlated with IIS. HFOs occurred during more behavioral states than IIS. Therefore, HFOs were the most abundant EEG abnormality, and this was generalizable across 3 types of preclinical AD.
PubMed: 37961135
DOI: 10.1101/2023.10.30.564797 -
International Journal of Molecular... Nov 2023Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer's disease (AD). In this study, we identified...
Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer's disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target's CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target.
Topics: Humans; Alzheimer Disease; Cannabidiol; Molecular Docking Simulation; Amyloid beta-Protein Precursor; Molecular Dynamics Simulation
PubMed: 37959001
DOI: 10.3390/ijms242116013 -
International Journal of Molecular... Oct 2023In Alzheimer's disease (AD), the age of onset (AoO) exhibits considerable variability, spanning from 40 to 90 years. Specifically, individuals diagnosed with AD and...
Potential Modifying Effect of the Allele on Age of Onset and Clinical Manifestations in Patients with Early-Onset Alzheimer's Disease with and without a Pathogenic Variant in in a Sample of the Mexican Population.
In Alzheimer's disease (AD), the age of onset (AoO) exhibits considerable variability, spanning from 40 to 90 years. Specifically, individuals diagnosed with AD and exhibiting symptoms prior to the age of 65 are typically classified as early onset (EOAD) cases. Notably, the apolipoprotein E (APOE) ε4 allele represents the most extensively studied genetic risk factor associated with AD. We clinically characterized and genotyped the allele from 101 individuals with a diagnosis of EOAD, and 69 of them were affected carriers of the autosomal dominant fully penetrant variant c.1292C>A (, A431E) (PSEN1+ group), while there were 32 patients in which the genetic cause was unknown (PSEN1- group). We found a correlation between the AoO and the allele; patients carrying at least one allele showed delays, in AoO in patients in the PSEN1+ and PSEN1- groups, of 3.9 ( = 0.001) and 8.6 years ( = 0.012), respectively. The PSEN1+ group presented higher frequencies of gait disorders compared to PSEN1- group, and apraxia was more frequent with PSEN1+/APOE4+ than in the rest of the subgroup. This study shows what appears to be an inverse effect of in EOAD patients, as it delays AoO and modifies clinical manifestations.
Topics: Adult; Aged; Aged, 80 and over; Humans; Middle Aged; Age of Onset; Alleles; Alzheimer Disease; Apolipoprotein E4; Genotype; Presenilin-1
PubMed: 37958671
DOI: 10.3390/ijms242115687 -
International Journal of Molecular... Oct 2023Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including...
Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder characterized by different pathological symptomatology, including disrupted circadian rhythm. The regulation of circadian rhythm depends on the light information that is projected from the retina to the suprachiasmatic nucleus in the hypothalamus. Studies of AD patients and AD transgenic mice have revealed AD retinal pathology, including amyloid-β (Aβ) accumulation that can directly interfere with the regulation of the circadian cycle. Although the cause of AD pathology is poorly understood, one of the main risk factors for AD is female gender. Here, we found that female APP/PS1 mice at 6- and 12-months old display severe circadian rhythm disturbances and retinal pathological hallmarks, including Aβ deposits in retinal layers. Since brain Aβ transport is facilitated by aquaporin (AQP)4, the expression of AQPs were also explored in APP/PS1 retina to investigate a potential correlation between retinal Aβ deposits and AQPs expression. Important reductions in AQP1, AQP4, and AQP5 were detected in the retinal tissue of these transgenic mice, mainly at 6-months of age. Taken together, our findings suggest that abnormal transport of Aβ, mediated by impaired AQPs expression, contributes to the retinal degeneration in the early stages of AD.
Topics: Mice; Humans; Female; Animals; Infant; Amyloid beta-Protein Precursor; Alzheimer Disease; Amyloid beta-Peptides; Mice, Transgenic; Retina; Aquaporin 4; Gene Expression; Disease Models, Animal; Presenilin-1; Plaque, Amyloid
PubMed: 37958666
DOI: 10.3390/ijms242115679