Reduced amyloid-β degradation in early Alzheimer's disease but not in the APPswePS1dE9 and 3xTg-AD mouse models

Aging Cell ◽  
2013 ◽  
Vol 12 (3) ◽  
pp. 499-507 ◽  
Author(s):  
Anita Stargardt ◽  
Judith Gillis ◽  
Willem Kamphuis ◽  
Anne Wiemhoefer ◽  
Lieneke Kooijman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Amyloid Β ◽  
Early Alzheimer’S Disease

Astrocyte Reactivity in Alzheimer’s Disease: Therapeutic Opportunities to Promote Repair

2021 ◽  
Vol 18 ◽  
Author(s):  
Nazanin Mirzaei ◽  
Nicola Davis ◽  
Tsz Wing Chau ◽  
Magdalena Sastre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Mouse Models ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Neuroprotective Effects ◽  
Synaptic Density ◽  
Inflammatory Profile

: Astrocytes are fast climbing the ladder of importance in neurodegenerative disorders, particularly in Alzheimer’s disease (AD), with the prominent presence of reactive astrocytes sur- rounding amyloid β- plaques, together with activated microglia. Reactive astrogliosis, implying morphological and molecular transformations in astrocytes, seems to precede neurodegeneration, suggesting a role in the development of the disease. Single-cell transcriptomics has recently demon- strated that astrocytes from AD brains are different from “normal” healthy astrocytes, showing dys- regulations in areas such as neurotransmitter recycling, including glutamate and GABA, and im- paired homeostatic functions. However, recent data suggest that the ablation of astrocytes in mouse models of amyloidosis results in an increase in amyloid pathology as well as in the inflammatory profile and reduced synaptic density, indicating that astrocytes mediate neuroprotective effects. The idea that interventions targeting astrocytes may have great potential for AD has therefore emerged, supported by a range of drugs and stem cell transplantation studies that have successfully shown a therapeutic effect in mouse models of AD. In this article, we review the latest reports on the role and profile of astrocytes in AD brains and how manipulation of astrocytes in animal mod- els has paved the way for the use of treatments enhancing astrocytic function as future therapeutic avenues for AD.

scholarly journals Amyloid-β protein modulates the perivascular clearance of neuronal apolipoprotein E in mouse models of Alzheimer’s disease

2011 ◽  
Vol 118 (5) ◽  
pp. 699-712 ◽  
Author(s):  
Harshvardhan Rolyan ◽  
Ann Caroline Feike ◽  
Ajeet Rijal Upadhaya ◽  
Andreas Waha ◽  
Tom Van Dooren ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Mouse Models ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein

P3-384: ASSOCIATION OF TAU AND AMYLOID-β PROTEINS TO STRUCTURAL CONNECTIVITY CHANGES IN COGNITIVELY HEALTHY ELDERLY AND EARLY ALZHEIMER'S DISEASE

2006 ◽  
Vol 14 (7S_Part_23) ◽  
pp. P1241-P1242
Author(s):  
Yoko Shigemoto ◽  
Daichi Sone ◽  
Masayo Ogawa ◽  
Harumasa Takano ◽  
Noriko Sato ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Connectivity ◽  
Amyloid Β ◽  
Healthy Elderly ◽  
Early Alzheimer’S Disease

scholarly journals Longitudinal plasma p-tau217 is increased in early stages of Alzheimer’s disease

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3234-3241 ◽  
Author(s):  
Niklas Mattsson-Carlgren ◽  
Shorena Janelidze ◽  
Sebastian Palmqvist ◽  
Nicholas Cullen ◽  
Anna L Svenningsson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Linear Mixed Effects ◽  
Three Samples ◽  
Longitudinal Plasma ◽  
Early Alzheimer’S Disease ◽  
Alzheimer’S Disease Dementia

Abstract Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer’s disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer’s disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β  =  0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β  =  0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer’s disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β  =  0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer’s disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer’s disease and can be used to monitor disease progression.

scholarly journals Ageing-associated myelin dysfunction drives amyloid deposition in mouse models of Alzheimer's disease

2021 ◽  
Author(s):  
Constanze Depp ◽  
Ting Sun ◽  
Andrew Octavian Sasmita ◽  
Lena Spieth ◽  
Stefan A. Berghoff ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Mouse Models ◽  
Structural Integrity ◽  
Amyloid Β ◽  
Amyloid Deposition ◽  
Structural Defects ◽  
Light Sheet Microscopy ◽  
Brain Ageing

The prevalence of Alzheimer's disease (AD), the leading cause of dementia, shows a strict age-dependency, but why ageing constitutes the main risk factor for this disease is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter associated with secondary neuroinflammation. Since oligodendrocytes support axonal and neuronal health, we hypothesised that ageing-associated loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the primary neuropathological hallmark of AD. Here, we show that in AD mouse models different genetically induced defects of myelin integrity or demyelinating injuries are indeed potent drivers of amyloid deposition in vivo, quantified by whole brain light sheet microscopy. Conversely, the lack of myelin in the forebrain provides protection against plaque deposition. Mechanistically, we find that myelin dysfunction causes the accumulation of the Aβ producing machinery within axonal swellings and increases cortical amyloid precursor protein (APP) cleavage. Surprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia but show a disease-associated microglia (DAM)-like signature as revealed by bulk and single cell transcriptomics. These activated microglia, however, are primarily engaged with myelin, preventing the protective reactions of microglia to Aβ plaques. Our data suggest a working model, in which age-dependent structural defects of myelin promote plaque formation, directly and indirectly, and are thus an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay AD.

scholarly journals Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in Alzheimer’s Disease Mouse Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Yulian Zou ◽  
Chen-Ling Gan ◽  
Zhiming Xin ◽  
Hai-Tao Zhang ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Mouse Models ◽  
Glycogen Synthase ◽  
Neuronal Damage ◽  
Amyloid Β ◽  
Glycogen Synthase Kinase ◽  
Tau Hyperphosphorylation

Alzheimer’s disease (AD) is a central nervous system degenerative disease, with no effective treatment to date. Administration of immune checkpoint inhibitors significantly reduces neuronal damage and tau hyperphosphorylation in AD, but the specific mechanism is unclear. Here, we found that programmed cell death-receptor 1 (PD1) and its ligand PDL1 were induced by an intracerebroventricular injection of amyloid-β; they were significantly upregulated in the brains of APP/PS1, 5×FAD mice and in SH-SY5Y-APP cell line compared with control. The PD1 and PDL1 levels positively correlated with the glycogen synthase kinase 3 beta (GSK3β) activity in various AD mouse models, and the PDL1-GSK3β immune complex was found in the brain. The application of PD1-blocking antibody reduced tau hyperphosphorylation and GSK3β activity and prevented memory impairments. Mechanistically, we identified PD1 as a critical regulator of GSK3β activity. These results suggest that the immune regulation of the PD1/PDL1 axis is closely involved in AD.

scholarly journals Automatic Prediction of Cognitive and Functional Decline Can Significantly Decrease the Number of Subjects Required for Clinical Trials in Early Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Neda Shafiee ◽  
Mahsa Dadar ◽  
Simon Ducharme ◽  
D. Louis Collins ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Decline ◽  
Functional Decline ◽  
Amyloid Β ◽  
Cognitive Test ◽  
Disease Heterogeneity ◽  
Early Alzheimer’S Disease

Background: While both cognitive and magnetic resonance imaging (MRI) data has been used to predict progression in Alzheimer’s disease, heterogeneity between patients makes it challenging to predict the rate of cognitive and functional decline for individual subjects. Objective: To investigate prognostic power of MRI-based biomarkers of medial temporal lobe atrophy and macroscopic tissue change to predict cognitive decline in individual patients in clinical trials of early Alzheimer’s disease. Methods: Data used in this study included 312 patients with mild cognitive impairment from the ADNI dataset with baseline MRI, cerebrospinal fluid amyloid-β, cognitive test scores, and a minimum of two-year follow-up information available. We built a prognostic model using baseline cognitive scores and MRI-based features to determine which subjects remain stable and which functionally decline over 2 and 3-year follow-up periods. Results: Combining both sets of features yields 77%accuracy (81%sensitivity and 75%specificity) to predict cognitive decline at 2 years (74%accuracy at 3 years with 75%sensitivity and 73%specificity). When used to select trial participants, this tool yields a 3.8-fold decrease in the required sample size for a 2-year study (2.8-fold decrease for a 3-year study) for a hypothesized 25%treatment effect to reduce cognitive decline. Conclusion: When used in clinical trials for cohort enrichment, this tool could accelerate development of new treatments by significantly increasing statistical power to detect differences in cognitive decline between arms. In addition, detection of future decline can help clinicians improve patient management strategies that will slow or delay symptom progression.

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