Impaired neuroinflammatory response of ApoE4 in Alzheimer's disease patients: Molecular and cell biology/neuroinflammation. (7th December 2020)

• Record Type: Journal Article
• Authors: Kloske, Courtney M.; Dugan, Adam; Woolums, Abigail E.; Lee, Tiffany; Anderson, Sonya; Patel, Ela; Abner, Erin L.; Nelson, Peter T; Fardo, David W.; Wilcock, Donna M
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.041052
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Amyloid plaques and neurofibrillary tangles distinguish Alzheimer's disease (AD) from other dementias. Additionally, there is a neuroinflammatory response to these hallmarks which induces the activation and proliferation of microglia. While this initially helps clear AD pathology, it can also lead to detrimental consequences depending on length of activation. In addition to the pathology, there are genetic risk factors for AD. One of the most influential is Apolipoprotein E (ApoE), a cholesterol and lipid transporter in the brain. There are three common isoforms: ApoE3 is believed to be the "control" phenotype, ApoE2 is believed to protect against AD, and ApoE4 to confer an increased risk for AD. Studies have shown that the ApoE isoforms have differing effects on many aspects of AD including, amyloid‐beta clearance and microglial activation. Method: We used the Human Neuroinflammation NanoString panel to assess the neuroinflammatory profile in the superior medial temporal gyrus (SMTG) and cerebellar regions of age and sex matched patients with the following genotypes and pathology: ApoE3/3‐AD (Braak V/VI, Thal 5) (N=9); ApoE4/4‐AD (Braak V/VI, Thal 5) (N=10); and ApoE3/3‐control (Braak I/II, Thal 0) (N=5). RNA was extracted from frozen SMTG, and cerebellum. Nanostring results were analyzed with NanoStringDiff followed by additional statistical analysis. qPCR was performed to verify results. Result: We first examined the inflammatory gene expression changes between ApoE3/3‐AD and ApoE3/3‐control patients to investigate differences that may be due to AD. Here we found significant gene changes specifically in pathways involved in microglial activation and apoptosis. Further, we examined differences between ApoE4/4‐AD and ApoE3/3‐control patients to determine the AD‐associated effects with ApoE4. These results showed no significant differences between the groups, suggesting that while ApoE4/4‐AD patients have both AD pathology and an impaired inflammatory response to the pathology. Next, we investigated ApoE3/3‐AD vs ApoE4/4‐AD to look at ApoE isoform‐associated effects with AD pathology. We found significant differences; however, the differences paralleled those between ApoE3/3‐AD and ApoE3/3‐control, once again suggesting ApoE4/4‐AD patients have an impaired inflammatory response to the pathology. Conclusion: These results suggest differences in the neuroinflammation between ApoE3/3 and ApoE4/4 patients with AD and may be implicated in disease progression.