46 research outputs found
Amyloid-b seeding and propagation processes in a hAb-KI model of Alzheimer's disease
Recent evidence indicates that Aβ can misfold and aggregate into seeds that
structurally corrupt native proteins, mimicking a prion-like process. Several
studies using FAD animal models have demonstrated that intracerebral
infusion of brain extracts from APP-transgenic mice or AD patients induce
Aβ deposition and cerebral amyloid angiopathy. To carry out most of these
Aβ-seeding studies, APP-transgenic animal have been used. Nevertheless, it
remains to be elucidated whether Aβ deposition can be induced by Aβ-seeds
in a sporadic AD model that does not overexpress APP and produces wild
type human Aβ.
We used an innovative model to better understand the amyloidogenic events
that occur in sporadic AD. This hAβ-KI model, expresses wild-type human
Aβ under the control of the endogenous mouse APP gene. Aβ-seeds from
AD patients (stage C) from the AD Research Center (UCI) were
administered into 7-8-month-old hAβ-KI and as positive controls 3xTg-AD
mice were employed.
We demonstrated that amyloid seeds can stimulate Aβ aggregations in
3xTg-AD and hAβ-KI models. We found that Aβ aggregates occur earlier
in the 3xTg-AD vs hAβ-KI and that a longer term of treatment is necessary
to accelerate diffusible Aβ pathology in the hAβ-KI mice. Thereferoe, this
hAβ-KI model represents an important step towards the development of
next-generation animal models that will provide better predictive outcomes
for human patients.
Grants support: UCI MIND Pilot project (DBV), Ministry of Science
PID2019-108911RA-100 (DBV), U54 AG054349 (FML), Institute of
Health Carlos III PI18/01557 (AG) co-financed by FEDER funds (European
Union), NIH/NIA Grant P50 AG16573 (UCI-ADRC).Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech
Human amyloid seeds aggregate more efficient than seeds from old 3xtg-ad mice
Aims: Most age-associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies in animal models show that the injection of brain homogenates from AD patients or from aged APP-transgenic mice containing Aβ aggregates, can induce some of the neuropathological hallmarks of AD. However, it is still unknown which Aβ-misfolded species are most efficient in triggering the aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg-AD model) is more efficient to generate amyloid aggregates. Methods: We employed histological and molecular approaches to determine amyloid level, species and aggregative capacity of brain homogenates from an AD patient (stage C for amyloid, from the Alzheimer’s Disease Research Center at UCI) vs old-3xTg-AD mice (25-month-old). Such brain homogenates were injected into the hippocampus of 7-month-old 3xTg-AD mice and the mice were analyzed at 18 months of age. Results: Our findings demonstrated that amyloid seeds from the human patient have more capacity to generate Aβ plaques vs seeds from aged 3xTg-AD mice. Conclusions: These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg-AD mice. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec
Human and mouse seeds differentially affect AB aggregation by modulating the inflammatory response.
Abstract text: Alzheimer’s Disease (AD) is a neurodegenerative proteinopathy in which Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prionlike process. These amyloid aggregation and propagation processes are influenced by three factors: the origin of the Aβ seed, time of incubation and host. However, the mechanism underlying the differential effect of each factor is poorly known. Previous studies have shown that the Aβ source is relevant for the amyloid process, since its pathogenicity is different according to its origin. Furthermore, recent evidence suggests that microglia plays a key role in the amyloidogenic event, and can modulate the propagation and aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg-AD model) are more efficient to generate amyloid aggregates, as well as the role of the microglia in the propagation process.
Methods: Amyloid seeds from AD patient (stage C for amyloid; from the Alzheimer’s Disease Research Center at UCI) and 25 mo-3xTg-AD mice were injected into the hippocampus of 7-8- month-old 3xTg-AD mice. They were analyzed 10 months post-surgery for amyloid and microglia markers.
Results: Our findings demonstrated that amyloid seeds from the human patient seem to induce a more aggressive amyloid pathology compared to seeds from aged 3xTg-AD mice. Moreover, human and mice seeds differentially affect the presence of plaque-associated microglia in 3xTgAD mice.
Conclusion: These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg-AD mice, and also microglia cells may play a key role in this differential effect. Therefore, more profound understanding these factors will provide key
insight on how amyloid pathology progresses in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech
Amyloid propagation in a sporadic model of Alzheimer disease
Most age-associated neurodegenerative disorders involve the aggregation of
specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent
evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt
native proteins, mimicking a prion-like process of template protein corruption or seeding. In
fact, studies in FAD-based animal models show that Aβ deposition and cerebral amyloid
angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or
from aged APP-transgenic mice. These studies have shown that the characteristic of both
the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this
regard, the majority of the Aβ-seeding studies have been done in APP-transgenic animal
models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ
deposition can be induced by Aβ seeds in an animal model that does not overexpress APP
and produces wild type human Aβ and if these aggregates are similar to the human
condition.
Here, we used an innovative animal model to better understand the
amyloidogenic events that occur in the sporadic form of the disease. Our model, termed
hAβ-KI, expresses wild-type human Aβ under the control of the endogenous mouse APP
gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s
Disease Research Center (ADRC) at UCI were administered into 7-8-month-old hAβ-KI and
as positive controls 3xTg-AD mice were employed.
Our findings demonstrated that amyloid seeds differentially occur in 3xTg-AD and
hAb-KI mice and these aggregates are developed earlier in the familial model, 3xTg-AD
mice.
These results suggest that multiple factors such as the seed, recipient model
and time are critical factors that can modulate the amyloid pathology onset and
progression. Thus, more profound understanding these factors will provide key insight on
how amyloid pathology progress in AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech
Human and mouse seeds differentially affect Aβ aggregation by modulating the inflammatory response
Background: Alzheimer’s Disease (AD) is a neurodegenerative proteinopathy in which Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process. These amyloid aggregation and propagation processes are influenced by three factors: the origin of the Aβ seed, time of incubation and host. However, the mechanism underlying the differential effect of each factor is poorly known. Previous studies have shown that the Aβ source is relevant for the amyloid process, since its pathogenicity is different according to its origin. Furthermore, recent evidence suggests that microglia plays a key role in the amyloidogenic event, and can modulate the propagation and aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg-AD model) are more efficient to generate amyloid aggregates, as well as the role of the microglia in the propagation process.
Method: Amyloid seeds from AD patient (stage C for amyloid; from the Alzheimer’s Disease Research Center at UCI) and 25 mo-3xTg-AD mice were injected into the hippocampus of 7-8-month-old 3xTg-AD mice. They were analyzed 10 months postsurgery for amyloid and microglia markers.
Result: Our findings demonstrated that amyloid seeds from the human patient seem to induce a more aggressive amyloid pathology compared to seeds from aged 3xTg-AD mice. Moreover, human and mice seeds differentially affect the presence of plaqueassociated microglia in 3xTg-AD mice.
Conclusion: These results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg-AD mice, and also microglia cells may play a key role in this differential effect. Therefore, more profound understanding these factors will provide key insight on how amyloid pathology progresses in AD.This study was supported by Minister of Science and Innovation grant PID2019-108911RA-100 (D.B.V.), Alzheimer’s Association grant AARG-22-928219 (D.B.V), Beatriz Galindo program BAGAL18/00052 (D.B.V.) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co-financed by FEDER funds from European Union
Model organism development and evaluation for late‐onset Alzheimer's disease: MODEL‐AD
Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease‐modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late‐onset Alzheimer's Disease (MODEL‐AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL‐AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging–supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide