Background: A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear.
Method: We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Mouse samples were collected and used for multiple measurements including cholesterol test, WB, ELISA, IF, etc. We also designed and performed in vitro assays to evaluate the phagocytosis, degradation, competitive uptake, exocytosis, etc. RESULT: APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans in vitro.
Conclusion: APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/alz.086126 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Basic Science and Pathogenesis.
Alzheimers Dement
December 2024
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Background: Heterogeneity in the progression of clinical dementia poses a significant challenge, impeding the effectiveness of current therapies for Alzheimer's disease (AD). To decipher the molecular mechanisms governing heterogeneity in AD progression that remains a critical knowledge gap precluding rational therapeutic design, we investigated the biochemical and biophysical properties of tau present in the inferior temporal gyrus (ITG) and prefrontal cortex (PFC) brain regions of AD patients who had varying disease progression rates. To explore gene expression changes in the ITG which are associated with tau pathology and cognitive decline, we used RNA sequencing for molecular characterization of patients displaying tau and clinical heterogeneity.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
Washington University School of Medicine, Saint Louis, MO, USA.
Background: A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear.
Method: We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model.
Basic Science and Pathogenesis.
Alzheimers Dement
December 2024
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, Shanghai, China.
Background: Pathological tau plays critical roles in many neurodegenerative diseases (NDD), including Alzheimer's disease (AD). However, the mechanisms underlying the initial tau pathogenesis are largely unknown. Extensive tau pathology has been observed in the brains with chronic traumatic encephalopathy (CTE), suggesting repeated traumatic brain injury (rTBI) correlates with tau pathogenesis.
View Article and Find Full Text PDFBasic Science and Pathogenesis.
Alzheimers Dement
December 2024
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
Article Synopsis
- Asymptomatic Alzheimer's disease (AsymAD) is characterized by the presence of Alzheimer's pathology in individuals who maintain cognitive function, showing lower neuroinflammation compared to symptomatic Alzheimer's disease cases.
- Research using postmortem brain samples revealed that AsymAD subjects have unique characteristics such as enriched core plaques and reduced tau aggregation, along with increased microglial activity around amyloid plaques.
- The study suggests that the composition of the plaque microenvironment, particularly enhanced actin-based motility pathways in microglia, may play a key role in the resilience to Alzheimer's pathology and cognitive decline in AsymAD individuals.
Basic Science and Pathogenesis.
Alzheimers Dement
December 2024
Purdue University, Lafayette, IN, USA.
Background: Alzheimer's disease (AD) is the leading cause of dementia, affecting 50 million people globally. Current AD animal models mainly focus on familial or inherited AD. These models often carry the APP and PSEN gene mutations from familial AD patients, or introduce microtubule-associated protein tau (MAPT) mutations, which can cause frontotemporal dementia but are not linked to AD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!