scholarly journals Staging Alzheimer’s disease in the brain and retina of B6.APP/PS1 mice by transcriptional profiling

2019 ◽  
Author(s):  
Sumana R. Chintapaludi ◽  
Asli Uyar ◽  
Harriet M. Jackson ◽  
Casey J. Acklin ◽  
Xulong Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Deposition ◽  
Central Component ◽  
Tau Pathology ◽  
Linear Modeling ◽  
Plaque Deposition ◽  
Mutant Forms ◽  
The Brain ◽  
Stat Pathway

ABSTRACTAlzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD.

scholarly journals Tau-Reactive Endogenous Antibodies: Origin, Functionality, and Implications for the Pathophysiology of Alzheimer’s Disease

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Lenka Hromadkova ◽  
Saak Victor Ovsepian
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Evaluation ◽  
Circulatory System ◽  
Peripheral Circulation ◽  
Protective Role ◽  
Tau Pathology ◽  
Systematic Analysis ◽  
Neurodegenerative Process ◽  
The Brain

In Alzheimer’s disease (AD), tau pathology manifested in the accumulation of intraneuronal tangles and soluble toxic oligomers emerges as a potential therapeutic target. Multiple anti-tau antibodies inhibiting the formation and propagation of cytotoxic tau or promoting its clearance and degradation have been tested in clinical trials, albeit with the inconclusive outcome. Antibodies against tau protein have been found both in the brain circulatory system and at the periphery, but their origin and role under normal conditions and in AD remain unclear. While it is tempting to assign them a protective role in regulating tau level and removal of toxic variants, the supportive evidence remains sporadic, requiring systematic analysis and critical evaluation. Herein, we review recent data showing the occurrence of tau-reactive antibodies in the brain and peripheral circulation and discuss their origin and significance in tau clearance. Based on the emerging evidence, we cautiously propose that impairments of tau clearance at the periphery by humoral immunity might aggravate the tau pathology in the central nervous system, with implication for the neurodegenerative process of AD.

scholarly journals Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression

2021 ◽  
Vol 22 (23) ◽  
pp. 13136
Author(s):  
Han Seok Koh ◽  
SangJoon Lee ◽  
Hyo Jin Lee ◽  
Jae-Woong Min ◽  
Takeshi Iwatsubo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Treatment Strategies ◽  
Tau Pathology ◽  
Memory Decline ◽  
Tnf Α ◽  
The Brain

Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.

scholarly journals Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer’s disease

2020 ◽  
Vol 52 (8) ◽  
pp. 1275-1287
Author(s):  
Seong Su Kang ◽  
Eun Hee Ahn ◽  
Keqiang Ye
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Strategy ◽  
Senile Plaques ◽  
Tau Pathology ◽  
Disease Modifying ◽  
Tau Aggregation ◽  
The Brain ◽  
Insight Into

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how δ-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of δ-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of δ-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.

scholarly journals Possible Mechanisms of Tau Spread and Toxicity in Alzheimer’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Huiqin Zhang ◽  
Yu Cao ◽  
Lina Ma ◽  
Yun Wei ◽  
Hao Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cellular Uptake ◽  
Current Evidence ◽  
Pathological Changes ◽  
Tau Pathology ◽  
Complex Process ◽  
Growing Body ◽  
The Brain

Tau is a protein that associates with microtubules (MTs) and promotes their assembly and stability. The protein loses its ability to bind MTs in tauopathies, and detached tau can misfold and induce the pathological changes that characterize Alzheimer’s disease (AD). A growing body of evidence indicates that tauopathies can spread between cells or connected regions. Pathological tau transmission in the brain of patients with AD and other tauopathies is due to the spread of various tau species along neuroanatomically connected regions in a “prion-like” manner. This complex process involves multiple steps of secretion, cellular uptake, transcellular transfer, and/or seeding, but the precise mechanisms of tau pathology propagation remain unclear. This review summarizes the current evidence on the nature of propagative tau species and the possible steps involved in the process of tau pathology spread, including detachment from MTs, degradations, and secretion, and discusses the different mechanisms underlying the spread of tau pathology.

scholarly journals Astrocytic Propagation of Tau in the Context of Alzheimer's Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Rebecca M. Fleeman ◽  
Elizabeth A. Proctor
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Significance ◽  
Glial Cells ◽  
Cell Type ◽  
Tau Pathology ◽  
Specific Effects ◽  
Signaling Mechanisms ◽  
Cell Type Specific ◽  
The Brain

More than 6 million Americans are currently living with Alzheimer's disease (AD), and the incidence is growing rapidly with our aging population. Numerous therapeutics have failed to make it to the clinic, potentially due to a focus on presumptive pathogenic proteins instead of cell-type-specific signaling mechanisms. The tau propagation hypothesis that inter-neuronal tau transfer drives AD pathology has recently garnered attention, as accumulation of pathological tau in the brain has high clinical significance in correlating with progression of cognitive AD symptoms. However, studies on tau pathology in AD are classically neuron-centric and have greatly overlooked cell-type specific effects of tau internalization, degradation, and propagation. While the contribution of microglia to tau processing and propagation is beginning to be recognized and understood, astrocytes, glial cells in the brain important for maintaining neuronal metabolic, synaptic, trophic, and immune function which can produce, internalize, degrade, and propagate tau are understudied in their ability to affect AD progression through tau pathology. Here, we showcase evidence for whether tau uptake by astrocytes may be beneficial or detrimental to neuronal health and how astrocytes and their immunometabolic functions may be key targets for future successful AD therapies.

scholarly journals Federated Morphometry Feature Selection for Hippocampal Morphometry Associated Beta-Amyloid and Tau Pathology

2021 ◽  
Vol 15 ◽  
Author(s):  
Jianfeng Wu ◽  
Qunxi Dong ◽  
Jie Zhang ◽  
Yi Su ◽  
Teresa Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Feature Selection ◽  
Brain Magnetic Resonance Imaging ◽  
Amyloid Β ◽  
Imaging Biomarkers ◽  
Lasso Regression ◽  
Tau Pathology ◽  
Hippocampal Morphometry ◽  
The Brain

Amyloid-β (Aβ) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimer’s disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of Aβ/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with Aβ/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts to understand hippocampal alterations that relate to Aβ/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI), and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89× speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal Aβ/tau. As potential biomarkers for Aβ/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between Aβ/tau burden and hippocampal morphometry.

scholarly journals Gut Inflammation Induced by Dextran Sulfate Sodium Exacerbates Amyloid-β Plaque Deposition in the App NL – G – F Mouse Model of Alzheimer’s Disease

2021 ◽  
pp. 1-20
Author(s):  
Mona Sohrabi ◽  
Heidi L. Pecoraro ◽  
Colin K. Combs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Wild Type ◽  
Gut Inflammation ◽  
Plaque Deposition ◽  
Brain Changes ◽  
The Brain

Background: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer’s disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. Objective: Determine whether colitis exacerbates AD-related brain changes. Methods: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and App NL - G - F mice at 6–10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). Results: Both wild type and App NL - G - F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ 1–40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated App NL - G - F mice compared to vehicle treated App NL - G - F mice. Conclusion: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aβ deposition via an IBD-like model system.

scholarly journals Use of Biomarkers in Ongoing Research Protocols on Alzheimer’s Disease

2020 ◽  
Vol 10 (3) ◽  
pp. 68 ◽  
Author(s):  
Marco Canevelli ◽  
Giulia Remoli ◽  
Ilaria Bacigalupo ◽  
Martina Valletta ◽  
Marco Toccaceli Blasi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phase 1 ◽  
Amyloid Deposition ◽  
Tau Pathology ◽  
Eligibility Criteria ◽  
Ongoing Research ◽  
Research Protocols ◽  
Ongoing Phase ◽  
Selection Of

The present study aimed to describe and discuss the state of the art of biomarker use in ongoing Alzheimer’s disease (AD) research. A review of 222 ongoing phase 1, 2, 3, and 4 protocols registered in the clinicaltrials.gov database was performed. All the trials (i) enrolling subjects with clinical disturbances and/or preclinical diagnoses falling within the AD continuum; and (ii) testing the efficacy and/or safety/tolerability of a therapeutic intervention, were analyzed. The use of biomarkers of amyloid deposition, tau pathology, and neurodegeneration among the eligibility criteria and/or study outcomes was assessed. Overall, 58.2% of ongoing interventional studies on AD adopt candidate biomarkers. They are mostly adopted by studies at the preliminary stages of the drug development process to explore the safety profile of novel therapies, and to provide evidence of target engagement and disease-modifying properties. The biologically supported selection of participants is mostly based on biomarkers of amyloid deposition, whereas the use of biomarkers as study outcomes mostly relies on markers of neurodegeneration. Biomarkers play an important role in the design and conduction of research protocols targeting AD. Nevertheless, their clinical validity, utility, and cost-effectiveness in the “real world” remain to be clarified.

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