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Brain Research Bulletin Dec 2023Patients with chronic pain often have cognitive impairment; this is especially true in elderly patients with neurodegenerative diseases such as Alzheimer's disease (AD),...
Patients with chronic pain often have cognitive impairment; this is especially true in elderly patients with neurodegenerative diseases such as Alzheimer's disease (AD), but the mechanism underlying this association remains unclear. This was addressed in the present study by investigating the effect of chronic neuropathic pain on hippocampal neurogenesis and cognitive impairment using amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice subjected to spared-nerve injury (SNI). The Von Frey test was performed to determine the mechanical threshold of mouse hind limbs after SNI. The Morris water maze test was used to evaluate spatial learning and memory. Doublecortin-positive (DCX), 5-bromo-2'-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and C-C motif chemokine ligand 2 (CCL2) neurons in the dentate gyrus of the hippocampus were detected by immunohistochemistry and immunofluorescence analysis. CCL2 and C-C chemokine receptor type 2 (CCR2) protein levels in the mouse hippocampus were analyzed by western blotting. The results showed that APP/PS1 mice with chronic neuropathic pain induced by SNI had significant learning and memory impairment. This was accompanied by increased CCL2 and CCR2 expression and decreases in the number of DCX, BrdU, and BrdU/NeuN neurons. These results suggest that chronic neuropathic pain is associated with cognitive impairment, which may be caused by CCL2/CCR2 signaling-mediated inhibition of hippocampal neurogenesis. Thus, therapeutic strategies that alleviate neuropathic pain can potentially slow cognitive decline in patients with AD and other neurodegenerative diseases.
Topics: Aged; Animals; Mice; Alzheimer Disease; Amyloid beta-Protein Precursor; Bromodeoxyuridine; Chemokines; Chronic Pain; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Ligands; Mice, Transgenic; Neuralgia; Neurodegenerative Diseases; Neurogenesis; Presenilin-1; Receptors, Chemokine; Chemokine CCL2; Receptors, CCR2
PubMed: 37931808
DOI: 10.1016/j.brainresbull.2023.110801 -
BioRxiv : the Preprint Server For... Jan 2024Mutations in are the most common cause of familial, early-onset Alzheimer's disease (AD), typically producing cognitive deficits in the fourth decade. A variant of ,...
Mutations in are the most common cause of familial, early-onset Alzheimer's disease (AD), typically producing cognitive deficits in the fourth decade. A variant of , was found associated with protection from both cognitive decline and Tau accumulation in a 70-year-old bearing the disease-causing mutation. The amino acid change in ApoE3ch is within the heparan sulfate (HS) binding domain of APOE, and purified APOEch showed dramatically reduced affinity for heparin, a highly sulfated form of HS. The physiological significance of is supported by studies of a mouse bearing a knock-in of this human variant and its effects on microglia reactivity and Aβ-induced Tau deposition. The studies reported here examine the function of heparan sulfate-modified proteoglycans (HSPGs) in cellular and molecular pathways affecting AD-related cell pathology in human cell lines and mouse astrocytes. The mechanisms of HSPG influences on dependent cell loss and pathology were evaluated in using knockdown of the presenilin homolog, , together with partial loss of function of , a homolog of , a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in cultured human cell lines, , and mouse astrocytes. RNAi of reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of , and . RNA-sequence analysis of human cells deficient in HS synthesis demonstrated effects on the transcriptome governing lipid metabolism, autophagy, and mitochondrial biogenesis and showed significant enrichment in AD susceptibility genes identified by GWAS. Neuron-directed knockdown of in produced cell loss in the brain and behavioral phenotypes, both suppressed by simultaneous reductions in mRNA levels. Abnormalities in mitochondria, liposome morphology, and autophagosome-derived structures in animals with knockdown were also rescued by simultaneous reduction of knockdown reversed dependent transcript changes in genes affecting lipid transport, metabolism, and monocarboxylate carriers. These findings support the direct involvement of HSPGs in AD pathogenesis.
PubMed: 38328107
DOI: 10.1101/2024.01.23.576895 -
Brain Research Bulletin Aug 2023Synapse loss is a major contributor to cognitive dysfunction in Alzheimer's disease (AD). Impairments in the expression and/or glutamate uptake activity of glia...
Ceftriaxone ameliorates hippocampal synapse loss by inhibiting microglial/macrophages activation in glial glutamate transporter-1 dependent manner in the APP/PS1 mouse model of Alzheimer's disease.
Synapse loss is a major contributor to cognitive dysfunction in Alzheimer's disease (AD). Impairments in the expression and/or glutamate uptake activity of glia glutamate transporter-1 (GLT-1) contribute to synapse loss in AD. Hence, targeting the restoration of GLT-1 activity may have potential for alleviating synapse loss in AD. Ceftriaxone (Cef) can upregulate the expression and glutamate uptake activity of GLT-1 in many disease models, including those for AD. The present study investigated the effects of Cef on synapse loss and the role of GLT-1 using APP/PS1 transgenic and GLT-1 knockdown APP/PS1 AD mice. Furthermore, the involvement of microglia in the process was investigated due to its important role in synapse loss in AD. We found that Cef treatment significantly ameliorated synapse loss and dendritic degeneration in APP/PS1 AD mice, evidenced by an increased dendritic spine density, decreased dendritic beading density, and upregulated levels of postsynaptic density protein 95 (PSD95) and synaptophysin. The effects of Cef were suppressed by GLT-1 knockdown in GLT-1/APP/PS1 AD mice. Simultaneously, Cef treatment inhibited ionized calcium binding adapter molecule 1 (Iba1) expression, decreased the proportion of CD11bCD45 cells, declined interleukin-6 (IL-6) content, and reduced the co-expression of Iba1 with PSD95 or synaptophysin in APP/PS1 AD mice. In conclusion, Cef treatment ameliorated synapse loss and dendritic degeneration in APP/PS1 AD mice in a GLT-1-dependent manner, and the inhibitory effect of Cef on the activation of microglia/macrophages and their phagocytosis for synaptic elements contributed to the mechanism.
Topics: Mice; Animals; Alzheimer Disease; Ceftriaxone; Microglia; Synaptophysin; Mice, Transgenic; Hippocampus; Glutamic Acid; Synapses; Macrophages; Disks Large Homolog 4 Protein; Amino Acid Transport System X-AG; Disease Models, Animal; Amyloid beta-Protein Precursor; Presenilin-1; Amyloid beta-Peptides
PubMed: 37301482
DOI: 10.1016/j.brainresbull.2023.110683 -
Cell Death & Disease May 2024Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer's disease (AD) related molecular actors including amyloid beta (Aβ) and...
Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer's disease (AD) related molecular actors including amyloid beta (Aβ) and recently the amyloid precursor protein-C terminal fragments (APP-CTFs). The efficacy of the mitophagy process in neurons relies on regulated mitochondrial transport along axons involving a complex molecular machinery. The contribution of the amyloid precursor protein (APP) and its derived fragments to the mitochondrial transport machinery alterations in AD have not been investigated before. We report herein a change of the expression of mitochondrial transport proteins (SNPH and Miro1), motor adapters (TRANK1 and TRAK2), and components of the dynein and kinesin motors (i.e., IC1,2 and Kif5 (A, B, C) isoforms) by endogenous APP and by overexpression of APP carrying the familial Swedish mutation (APPswe). We show that APP-CTFs and Aβ concomitantly regulate the expression of a set of transport proteins as demonstrated in APPswe cells treated with β- and γ-secretase inhibitors and in cells Knock-down for presenilin 1 and 2. We further report the impact of APP-CTFs on the expression of transport proteins in AAV-injected C99 mice brains. Our data also indicate that both Aβ oligomers (Aβo) and APP-CTFs impair the colocalization of mitochondria and transport proteins. This has been demonstrated in differentiated SH-SY5Y naive cells treated with Aβo and in differentiated SH-SY5Y and murine primary neurons expressing APPswe and treated with the γ-secretase inhibitor. Importantly, we uncover that the expression of a set of transport proteins is modulated in a disease-dependent manner in 3xTgAD mice and in human sporadic AD brains. This study highlights molecular mechanisms underlying mitochondrial transport defects in AD that likely contribute to mitophagy failure and disease progression.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Mitochondria; Humans; Mice; Mice, Transgenic; Neurons; Amyloid beta-Peptides; Mitochondrial Proteins; Amyloid Precursor Protein Secretases; Kinesins; Biological Transport; Mitophagy; Nerve Tissue Proteins; rho GTP-Binding Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 38806484
DOI: 10.1038/s41419-024-06742-2 -
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 -
Cell Death & Disease Mar 2024Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of mA modifications in various...
Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of mA modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3-knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA mA methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of mA-modified PSEN1, while decreased METTL3-mediated mA methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.
Topics: Animals; beta Catenin; Methylation; Methyltransferases; RNA, Messenger; Wnt Signaling Pathway; Zebrafish; Presenilin-1; Zebrafish Proteins
PubMed: 38509077
DOI: 10.1038/s41419-024-06606-9 -
Journal of Cellular and Molecular... Nov 2023It is known that oxidative stress originating from reactive oxygen species plays a role in the pathogenesis of Alzheimer's disease. In this study, the role of...
It is known that oxidative stress originating from reactive oxygen species plays a role in the pathogenesis of Alzheimer's disease. In this study, the role of antioxidant status associated with oxidative stress in Alzheimer's disease was investigated. Peripheral blood samples were obtained from 28 healthy individuals (as control) and 28 Alzheimer's patients who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. Catalase, glutathione S-transferase and paraoxonase 1 enzyme activities in blood plasma and glutathione S-transferase enzyme activities in erythrocytes were determined by spectrophotometer. Catalase, glutathione S-transferase and presenilin 1 gene expressions in leukocytes were determined using qRT-PCR. Data were analysed with SPSS one-way anova, a LSD post hoc test at p < 0.05. The activity of each enzyme was significantly reduced in Alzheimer's patients compared to control. The catalase gene expression level did not change compared to the control. Glutathione S-transferase and presenilin 1 gene expression levels were increased compared to the control.
Topics: Humans; Antioxidants; Alzheimer Disease; Catalase; Presenilin-1; Oxidative Stress; Glutathione Transferase; Gene Expression
PubMed: 37772794
DOI: 10.1111/jcmm.17953 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of L. It is also used... (Review)
Review
Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use.
PubMed: 38675438
DOI: 10.3390/ph17040478 -
Journal of Alzheimer's Disease : JAD 2024Impaired odor identification is a characteristic of sporadic Alzheimer'sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain.
BACKGROUND
Impaired odor identification is a characteristic of sporadic Alzheimer'sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain.
OBJECTIVE
To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease.
METHODS
Participants from six families with autosomal-dominant mutations (APP Swedish, APP Arctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification.
RESULTS
MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC.
CONCLUSIONS
Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD.
Topics: Humans; Alzheimer Disease; Odorants; Cognitive Dysfunction; Cognition; Mutation; Presenilin-1
PubMed: 38160354
DOI: 10.3233/JAD-230618 -
International Journal of Molecular... Sep 2023Intramembrane proteases, such as γ secretase, typically recruit multiple substrates from an excess of single-span membrane proteins. It is currently unclear to which...
Intramembrane proteases, such as γ secretase, typically recruit multiple substrates from an excess of single-span membrane proteins. It is currently unclear to which extent substrate recognition depends on specific interactions of their transmembrane domains (TMDs) with TMDs of a protease. Here, we investigated a large number of potential pairwise interactions between TMDs of γ secretase and a diverse set of its substrates using two different configurations of BLaTM, a genetic reporter system. Our results reveal significant interactions between TMD2 of presenilin, the enzymatic subunit of γ secretase, and the TMD of the amyloid precursor protein, as well as of several other substrates. Presenilin TMD2 is a prime candidate for substrate recruitment, as has been shown from previous studies. In addition, the amyloid precursor protein TMD enters interactions with presenilin TMD 4 as well as with the TMD of nicastrin. Interestingly, the Gly-rich interfaces between the amyloid precursor protein TMD and presenilin TMDs 2 and 4 are highly similar to its homodimerization interface. In terms of methodology, the economics of the newly developed library-based method could prove to be a useful feature in related future work for identifying heterotypic TMD-TMD interactions within other biological contexts.
PubMed: 37762696
DOI: 10.3390/ijms241814396