Identification of early-onset photoreceptor degeneration in transgenic mouse models of Alzheimer's disease
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ABSTRACT:
SUBMITTER: Zhang J
PROVIDER: S-EPMC8581578 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:An early and sizeable loss of basal forebrain cholinergic neurons is a well-characterized feature associated with measurable deficits in spatial learning and cognitive impairment in patients with Alzheimer's disease. In addition, pro-inflammatory glial cells such as astrocytes and microglia may play a key role in the neurodegenerative cascade of Alzheimer's disease and tauopathies. We recently presented two mouse models: Line 1, expressing the truncated tau fragment identified as the core of the Alzheimer's paired helical filament, and Line 66, expressing full-length human tau carrying a double mutation (P301S and G335D). Line 1 mice have a pathology that is akin to Alzheimer's, whilst Line 66 resembles frontotemporal lobar degeneration. However, their cholinergic and inflammatory phenotypes remain elusive. We performed histological evaluation of choline acetyltransferase, acetylcholinesterase, p75 neurotrophin receptor, microglial ionized calcium binding adaptor molecule 1 and astrocytic glial fibrillary acidic protein in the basal forebrain, hippocampus and cortex of these models. A significant lowering of choline acetyltransferase-positive neurons and p75-positive neurons in the basal forebrain of Line 1 at 3, 6 and 9 months was observed in two independent studies, alongside a significant decrease in acetylcholinesterase staining in the cortex and hippocampus. The reductions in choline acetyltransferase positivity varied between 30% and 50% at an age when Line 1 mice show spatial learning impairments. Furthermore, an increase in microglial ionized calcium binding adaptor molecule 1 staining was observed in the basal forebrain, hippocampus and entorhinal cortex of Line 1 at 6 months. Line 66 mice displayed an intact cholinergic basal forebrain, and no difference in p75-positive neurons at 3 or 9 months. In addition, Line 66 exhibited significant microglial ionized calcium binding adaptor molecule 1 increase in the basal forebrain and hippocampus, suggesting a prominent neuroinflammatory profile. Increased concentrations of microglial interleukin-1β and astrocytic complement 3 were also seen in the hippocampus of both Line 1 and Line 66. The cholinergic deficit in Line 1 mice confirms the Alzheimer's disease-like phenotype in Line 1 mice, whilst Line 66 revealed no measurable change in total cholinergic expression, a phenotypic trait of frontotemporal lobar degeneration. These two transgenic lines are therefore suitable for discriminating mechanistic underpinnings between the Alzheimer's and frontotemporal lobar degeneration-like phenotypes of these mice.
| S-EPMC7425524 | biostudies-literature
Project description:Alzheimer's disease (AD) is the leading cause of dementia. The relationship between AD and sleep dysfunction has received increased attention over the past decade. The use of genetically engineered mouse models with enhanced production of amyloid beta (Aβ) or hyperphosphorylated tau has played a critical role in the understanding of the pathophysiology of AD. However, their revelations regarding the progression of sleep impairment in AD have been highly dependent on the mouse model used and the specific techniques employed to examine sleep. Here, we discuss the sleep disturbances and general pathology of 15 mouse models of AD. Sleep disturbances covered in this review include changes to NREM and REM sleep duration, bout lengths, bout counts and power spectra. Our aim is to describe in detail the severity and chronology of sleep disturbances within individual mouse models of AD, as well as reveal broader trends of sleep deterioration that are shared among most models. This review also explores a variety of potential mechanisms relating Aβ accumulation and tau neurofibrillary tangles to the progressive deterioration of sleep observed in AD. Lastly, this review offers perspective on how study design might impact our current understanding of sleep disturbances in AD and provides strategies for future research.
| S-EPMC10235623 | biostudies-literature
Project description:BackgroundMitochondrial dysfunction, oxidative damage and the accumulation of somatic mutations in mitochondrial DNA (mtDNA) have been associated with certain neurodegenerative disorders. Previous studies have also provided controversial results on the association of mtDNA haplogroups with susceptibility to Alzheimer's disease (AD), but possible relationships between mtDNA and frontotemporal lobar degeneration (FTLD) have been less frequently studied.MethodsWe analysed the role of mtDNA and its maintenance enzymes in 128 early-onset AD (eoAD) and in 66 FTLD cases. Patients and 99 controls were collected from a defined region of Finland, that of Northern Ostrobothnia, for the determination of mtDNA haplogroups and the analysis of two common mtDNA mutations (m.3243A>G, m.8344A>G). In addition, screening was performed for five common POLG1 mutations (T251I, A467T, P587L, W748S and Y955C) and all the coding exons of the PEO1 and ANT1 genes were screened for mutations.ResultsThe frequency of haplogroup cluster IWX was 2.3 fold higher among the FTLD cases than in the controls (OR 2.69, 95% CI 1.09-6.65, p = 0.028). The frequency of mtDNA haplogroups or clusters did not differ between the eoAD cases and controls. The two mtDNA mutations and five POLG1 mutations were absent in the eoAD and FTLD patients. No pathogenic mutations were found in the PEO1 or ANT1 genes.ConclusionsWe conclude that the haplogroup cluster IWX was associated with FTLD in our cohort. Further studies in other ethnically distinct cohorts are needed to clarify the contribution of mtDNA haplogroups to FTLD and AD.
| S-EPMC2830999 | biostudies-literature
Project description:PurposePhotoreceptor degeneration (PRD) is a genetically heterogeneous retinal disorder. Although a number of genes involved in PRD have been identified, their genetic basis remains unknown in a significant number of patients. In this study, we aimed to identify novel disease-causing genes of PRD.MethodsComprehensive ocular examinations were performed in a 2-year-old patient diagnosed with early onset PRD. Retinal capture sequencing was performed to screen causative mutations in known retinal disease-causing loci. Whole-exome sequencing (WES) and a series of variant-filtering strategies were applied for identifying novel disease-causing genes. Retina ATF6 expression was confirmed by immunohistochemistry. RT-PCR was performed to identify ATF6 mRNA in the patient.ResultsThe patient showed typical PRD features, with macular involvement and ellipsoid zone irregularities. Results of retinal capture sequencing were negative. WES data led to identification of biallelic loss-of-function mutations in the ATF6 gene. The first variant generates a premature stop codon (NCBI accession no. NM_007348: c.1126C>T, p.R376*) and the second variant affects a splicing donor site (NM_007348: c.1533+1G>C). Sanger sequencing confirmed the 2 alleles are from 1 parent each. Both of the variants are extremely rare in the population. The splicing variant causes either intron inclusion or exon skipping in the patient, thus severely disrupting ATF6 functional domains. ATF6 is expressed in three neuronal cell layers of mouse retina.ConclusionsOur results support ATF6 as a novel disease-causing gene for PRD and suggest that disrupted protein quality control mechanisms may be a novel pathological mechanism underlying human retinal degeneration.
| S-EPMC4468593 | biostudies-literature
Project description:Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.
| S-EPMC7227028 | biostudies-literature
Project description:There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polβ+/-. The 3xTgAD/Polβ+/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ+/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD.
| S-EPMC10948084 | biostudies-literature
Project description:Retinitis pigmentosa (RP) is a family of inherited diseases causing progressive photoreceptor death. Retinal ganglion cells (RGCs) form the biological substrate for various therapeutic approaches designed to restore vision in RP individuals. Assessment of survival and preservation of RGCs in animal paradigms mimicking the human disease is of key importance for appropriate implementation of vision repair strategies. Here we studied the survival of RGCs in the rd1 mutant mouse, a known model of early onset, autosomic recessive RP, at various stages of photoreceptor degeneration. Furthermore, we analyzed the morphology of various types of RGCs using the newly generated transgenic mouse rd1/Thy1-GFP, in which the rd1 mutation is associated with green fluorescent protein (GFP) expression in a small population of different RGCs. We found excellent survival of cells at up to 1 year of age, a time at which the inner retina is known to have severely reorganized and partially degenerated. However, 50% of the cells analyzed within all RGC types exhibit an undersized dendritic tree, spanning about half of the normal area. Undersized cells are found both in adult and in very young (1-month-old) mice. This suggests that their aberrant phenotype is due to incomplete dendritic development, possibly as a consequence of altered visual input at the time of dendritic arbor refinement. These data show the importance of the timing of photoreceptor death in RGC dendritic development.
| S-EPMC4112223 | biostudies-literature
Project description:Mints/X11s are neuronal adaptor proteins that bind to amyloid-beta precursor protein (APP). Previous studies suggested that Mint/X11 proteins influence APP cleavage and affect production of pathogenic amyloid-beta (Abeta) peptides in Alzheimer's disease; however, the biological significance of Mint/X11 binding to APP and their possible role in Abeta production remain unclear. Here, we crossed conditional and constitutive Mint1, Mint2, and Mint3 knock-out mice with transgenic mouse models of Alzheimer's disease overproducing human Abeta peptides. We show that deletion of all three individual Mint proteins delays the age-dependent production of amyloid plaque numbers and Abeta40 and Abeta42 levels with loss of Mint2 having the largest effect. Acute conditional deletion of all three Mints in cultured neurons suppresses the accumulation of APP C-terminal fragments and the secretion of ectodomain APP by decreasing beta-cleavage but does not impair subsequent gamma-cleavage. These results suggest that the three Mint/X11 proteins regulate Abeta production by a novel mechanism that may have implications for therapeutic approaches to altering APP cleavage in Alzheimer's disease.
| S-EPMC2693334 | biostudies-literature
Project description:BACKGROUND: Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Abeta. METHODS: Organotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system. Soluble and insoluble forms of Abeta were quantified and Abeta-cytokine relationships were analyzed. RESULTS: Compared to control littermates, transgenic mice showed a significant increase in the following pro-inflammatory cytokines: TNF-alpha, IL-6, IL-12p40, IL-1beta, IL-1alpha and GM-CSF. TNF-alpha, IL-6, IL-1alpha and GM-CSF showed a sequential increase from control to TgAPPsw to PS1/APPsw suggesting that the amplitude of this cytokine response is dependent on brain Abeta levels, since PS1/APPsw mouse brains accumulate more Abeta than TgAPPsw mouse brains. Quantification of Abeta levels in the same slices showed a wide range of Abeta soluble:insoluble ratio values across TgAPPsw and PS1/APPsw brain slices. Abeta-cytokine correlations revealed significant relationships between Abeta1-40, 1-42 (both soluble and insoluble) and all the above cytokines that changed in the brain slices. CONCLUSION: Our data confirm that the brains of transgenic APPsw and PS1/APPsw mice are under an active inflammatory stress, and that the levels of particular cytokines may be directly related to the amount of soluble and insoluble Abeta present in the brain suggesting that pathological accumulation of Abeta is a key driver of the neuroinflammatory response.
| S-EPMC555557 | biostudies-literature
Project description:Purpose:To validate the application of a known transgenic mouse line with green fluorescent cones (Chrnb4.EGFP) to study cone photoreceptor biology and function in health and disease. Methods:Chrnb4.EGFP retinas containing GFP+ cones were compared with retinas without the GFP transgene via immunohistochemistry, quantitative real-time polymerase chain reaction, electroretinograms, and flow cytometry. The Chrnb4.EGFP line was backcrossed to the mouse models of cone degeneration, Pde6ccpfl1 and Gnat2cpfl3 , generating the new lines Gnat2.GFP and Pde6c.GFP, which were also studied as described. Results:GFP expression spanned the length of the cone cell in the Chrnb4.EGFP line, as well as in the novel Gnat2.GFP and Pde6c.GFP lines. The effect of GFP expression showed no significant changes to outer nuclear layer cell death, cone-specific gene expression, and immune response activation. A temporal decrease in GFP expression over time was observed, but GFP fluorescence was still detected through flow cytometry as late as 6 months. Furthermore, a functional analysis of photopic and scotopic electroretinogram responses of the Chrnb4 mouse showed no significant difference between GFP- and GFP+ mice, whereas electroretinogram recordings for the Pde6c.GFP and Gnat2.GFP lines matched previous reports from the original lines. Conclusions:This study demonstrates that the Chrnb4.EGFP mouse can be a powerful tool to overcome the limitations of studying cone biology, including the use of this line to study different types of cone degeneration. Translational Relevance:This work validates research tools that could potentially offer more reliable preclinical data in the development of treatments for cone-mediated vision loss conditions, shortening the gap to clinical translation.
| S-EPMC7442867 | biostudies-literature