scholarly journals Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ceren Emre ◽  
Khanh V. Do ◽  
Bokkyoo Jun ◽  
Erik Hjorth ◽  
Silvia Gómez Alcalde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Imaging ◽  
Cell Activation ◽  
Glial Activation ◽  
Receptor Expression ◽  
Biosynthetic Enzymes ◽  
Bioactive Lipids ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

AbstractSustained brain chronic inflammation in Alzheimer’s disease (AD) includes glial cell activation, an increase in cytokines and chemokines, and lipid mediators (LMs), concomitant with decreased pro-homeostatic mediators. The inflammatory response at the onset of pathology engages activation of pro-resolving, pro-homeostatic LMs followed by a gradual decrease. We used an APP knock-in (App KI) AD mouse that accumulates β-amyloid (Aβ) and presents cognitive deficits (at 2 and 6 months of age, respectively) to investigate LMs, their precursors, biosynthetic enzymes and receptors, glial activation, and inflammatory proteins in the cerebral cortex and hippocampus at 2-, 4-, 8- and 18-month-old in comparison with wild-type (WT) mice. We used LC-mass-spectrometry and MALDI molecular imaging to analyze LMs and phospholipids, and immunochemistry for proteins. Our results revealed an age-specific lipid and cytokine profile, and glial activation in the App KI mice. Despite an early onset of Aβ pathology, pro-inflammatory and pro-resolving LMs were prominently increased only in the oldest age group. Furthermore, the LM biosynthetic enzymes increased, and their receptor expression decreased in the aged App KI mice. Arachidonic acid (AA)-containing phospholipid molecular species were elevated, correlating with decreased cPLA2 activity. MALDI molecular imaging depicted differential distribution of phospholipids according to genotype in hippocampal layers. Brain histology disclosed increased microglia proliferation starting from young age in the App KI mice, while astrocyte numbers were enhanced in older ages. Our results demonstrate that the brain lipidome is modified preferentially during aging as compared to amyloid pathology in the model studied here. However, alterations in phospholipids signal early pathological changes in membrane composition.

scholarly journals Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Priyanka Joshi ◽  
Michele Perni ◽  
Ryan Limbocker ◽  
Benedetta Mannini ◽  
Sam Casford ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unfolded Protein Response ◽  
Neurodegenerative Disorders ◽  
C Elegans ◽  
Unfolded Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Parkinson’S Diseases ◽  
Protein Response

AbstractAge-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.

P1-031: Age-related cerebral changes of brain-derived neurotrophic factor in a model of Alzheimer's disease in APP23 transgenic mice

2006 ◽  
Vol 2 ◽  
pp. S103-S103
Author(s):  
Olaf Schulte-Herbrüggen ◽  
Uwe Deicke ◽  
Uwe Otten ◽  
Dorothee Abramowski ◽  
Matthias Staufenbiel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease

2016 ◽  
Vol 58 ◽  
pp. 191-200 ◽  
Author(s):  
Claire L. McDonald ◽  
Edel Hennessy ◽  
Ana Rubio-Araiz ◽  
Brian Keogh ◽  
William McCormack ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Glial Activation ◽  
Model Of Alzheimer’S Disease ◽  
Amyloid Accumulation ◽  
Tlr2 Activation

scholarly journals Sex-specific interactions between procedural and deliberative decision-making systems in a mouse model of Alzheimer’s disease

2021 ◽  
Author(s):  
Rachel Anderson ◽  
Damyan W. Hart ◽  
Brian Sweis ◽  
Mathew A. Sherman ◽  
Mark J. Thomas ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Decision Making ◽  
Mouse Model ◽  
Neural Substrates ◽  
Behavioral Changes ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Accurate Picture ◽  
And Control

AbstractA central question in aging and Alzheimer’s disease (AD) is when and how neural substrates underlying decision-making are altered. Here we show that while APP mice, a commonly used mouse model of AD, were able to learn Restaurant Row, a complex neuroeconomic decision-making task, they were significantly impaired in procedural, habit-forming, aspects of cognition and relied heavily on deliberation when making decisions. Surprisingly, these behavioral changes are associated with amyloid-beta (Aβ) pathology and network remodeling in the striatum, a key brain region involved in procedural cognition. Furthermore, APP mice and control mice relied on distinct sex-specific strategies in this neuroeconomic task. These findings provide foundational pillars to examine how aging and age-related neurodegenerative diseases impact decision-making across sexes. They also highlight the need for complex behavioral tasks that allow for the dissociation of competing neurally-distinct decision-making circuits to get an accurate picture of changes in neurodegenerative models of human disease.

scholarly journals Elevated age-related cortical iron, ferritin and amyloid plaques in APPswe/PS1ΔE9 transgenic mouse model of Alzheimer’s disease

2019 ◽  
pp. S445-S451 ◽  
Author(s):  
H. Svobodová ◽  
D. Kosnáč ◽  
Z. Balázsiová ◽  
H. Tanila ◽  
P.O. Miettinen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Amyloid Plaque ◽  
Free Iron ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Concentration Changes ◽  
The Brain ◽  
Important Marker

Iron is very important element for functioning of the brain. Its concentration changes with aging the brain or during disease. The aim of our work was the histological examination of content of ferritin and free iron (unbound) in brain cortex in association with Aβ plaques from their earliest stages of accumulation in amyloid plaque forming APP/PS1 transgenic mice. Light microscopy revealed the onset of plaques formation at 8-monthage. Detectable traces of free iron and no ferritin were found around plaques at this age, while the rate of their accumulation in and around Aβ plaques was elevated at 13 months of age. Ferritin accumulated mainly on the edge of Aβ plaques, while the smaller amount of free iron was observed in the plaque-free tissue, as well as in and around Aβ plaques. We conclude that free iron and ferritin accumulation follows the amyloid plaques formation. Quantification of cortical iron and ferritin content can be an important marker in the diagnosis of Alzheimer’s disease.

Sexual dimorphism in behavior, neuropathology, and biomarkers in a tau P301S mouse model of Alzheimer’s disease

2019 ◽  
Author(s):  
Yao Sun ◽  
Yongqing Guo ◽  
Xuejian Feng ◽  
Meng Jia ◽  
Ning Ai ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Sexual Dimorphism ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Building Performance ◽  
Inflammatory Protein ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Therapeutic Development

Abstract Tau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content. Method: We systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology and biomarkers in plasma and brain. Results: Male P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205 and astrocyte activation compared to that of wild type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris Water Maze and open field test. In addition, we characterized the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 and the absense of macrophage-inflammatory protein (MIP)-3α. Male P301S transgenic mice expressed more plasma biomarkers than those of female P301S mice. Conclusion: Our findings highlight sexual dimorphism in the behavior, neuropathology, and biomarkers in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies.

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