Hypothesis: Modulation of microglial phenotype in Alzheimer's disease drives neurodegeneration

2021 ◽  
Author(s):  
Andrew G. Murchison
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Phenotype

scholarly journals Neuroinflammation characterizes the earliest changes in Alzheimer’s disease pathology and associated subjective cognitive impairment in adult hydrocephalus biopsies

2020 ◽  
Author(s):  
Wenrui Huang ◽  
Anne Marie Bartosch ◽  
Harrison Xiao ◽  
Xena Flowers ◽  
Sandra Leskinen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Status ◽  
Subjective Cognitive Decline ◽  
Cognitive Symptoms ◽  
Microglial Phenotype ◽  
Neuronal Genes ◽  
Early Alzheimer’S Disease ◽  
Disease Associated Genes ◽  
Microglial Response

AbstractIn an effort to better characterize the transcriptomic changes that accompany early Alzheimer’s disease (AD) pathology in living patients and correlate with contemporaneous cognitive data, we performed RNA-seq on 106 cortical biopsies that were taken during shunt placement for adult onset hydrocephalus with varying degrees of comorbid AD pathology. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of β-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Interestingly, downregulation of homeostatic genes and upregulation of disease-associated genes also correlate with microglial plaque invasion and an activated microglial morphology, and this change is not sensitive to cognitive status, suggesting that an initial microglial response to AD pathology is eventually maladaptive. Taken together, these findings highlight a restricted set of microglial and non-microglial genes and suggest that early AD pathology is largely characterized by a loss of homeostatic genes and an activated microglial phenotype that continues to evolve in conjunction with accumulating AD pathology in the setting of subjective cognitive decline.

scholarly journals APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease

2016 ◽  
Vol 36 (32) ◽  
pp. 8471-8486 ◽  
Author(s):  
G. D. Manocha ◽  
A. M. Floden ◽  
K. Rausch ◽  
J. A. Kulas ◽  
B. A. McGregor ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Microglial Phenotype

Alzheimer’s Disease Genetics: A Dampened Microglial Response?

2021 ◽  
pp. 107385842110245
Author(s):  
Zena K. Chatila ◽  
Elizabeth M. Bradshaw
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Innate Immune ◽  
Regulatory Mechanisms ◽  
Innate Immune Cells ◽  
Genetic Studies ◽  
Age Related ◽  
Microglial Phenotype ◽  
The Central Nervous System ◽  
Microglial Response

Alzheimer’s disease (AD) is a debilitating age-related neurodegenerative condition. Unbiased genetic studies have implicated a central role for microglia, the resident innate immune cells of the central nervous system, in AD pathogenesis. On-going efforts are clarifying the biology underlying these associations and the microglial pathways that are dysfunctional in AD. Several genetic risk factors converge to decrease the function of activating microglial receptors and increase the function of inhibitory receptors, resulting in a seemingly dampened microglial phenotype in AD. Moreover, many of these microglial proteins that are genetically associated with AD appear to interact and share pathways or regulatory mechanisms, presenting several points of convergence that may be strategic targets for therapeutic intervention. Here, we review some of these studies and their implications for microglial participation in AD pathogenesis.

scholarly journals Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease

2021 ◽  
Author(s):  
Ruth E. Jones ◽  
Robert Andrews ◽  
Peter Holmans ◽  
Matthew Hill ◽  
Philip R. Taylor
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Interferon Response ◽  
Risk Variants ◽  
Microglial Phenotype ◽  
Risk Snps ◽  
Transcriptomic Changes

AbstractGenetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests altered levels of SPi1 may alter microglial phenotype potentially impacting AD. This study determined how the mouse microglial transcriptome was altered following modest changes to Spi1 expression in primary microglia. RNA-sequencing was performed on microglia with reduced or increased Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by Spi1. In summary, a reduction in microglial Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194 Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of Spi1. Together these results suggest Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related Spi1 risk SNPs.

scholarly journals An immune response characterizes early Alzheimer’s disease pathology and subjective cognitive impairment in hydrocephalus biopsies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wenrui Huang ◽  
Anne Marie Bartosch ◽  
Harrison Xiao ◽  
Suvrajit Maji ◽  
Elliot H. H. Youth ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Normal Pressure ◽  
Subjective Cognitive Decline ◽  
Cognitive Symptoms ◽  
Rna Seq ◽  
Microglial Phenotype ◽  
Neuronal Genes ◽  
Β Amyloid ◽  
Early Alzheimer’S Disease

AbstractEarly Alzheimer’s disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy β-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.

scholarly journals Patterns of Expression of Purinergic Receptor P2RY12, a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer’s Disease Brains

2020 ◽  
Vol 21 (2) ◽  
pp. 678 ◽  
Author(s):  
Douglas G. Walker ◽  
Tiffany M. Tang ◽  
Anarmaa Mendsaikhan ◽  
Ikuo Tooyama ◽  
Geidy E. Serrano ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Purinergic Receptor ◽  
Pathological Process ◽  
Middle Temporal Gyrus ◽  
Reactive Microglia ◽  
Activated Microglia ◽  
Hla Dr ◽  
Microglial Phenotype ◽  
Putative Marker

Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer’s disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach with the goal of characterizing the distribution of purinergic receptor P2RY12-positive microglia, a marker previously defined as identifying homeostatic or non-activated microglia. We examined the expression of P2RY12 by dual-color light and fluorescence immunohistochemistry using sections of middle temporal gyrus from AD, high plaque and low plaque non-demented cases in relation to amyloid beta (Aβ) plaques and phosphorylated tau, markers of pathology, and HLA-DR, IBA-1, CD68, and progranulin, microglial phenotype markers. In low plaque cases, P2RY12-positive microglia mostly had non-activated morphologies, while the morphologies of P2RY12-positive microglia in AD brains were highly variable, suggesting its expression could encompass a wider range of phenotypes than originally hypothesized. P2RY12 expression by microglia differed depending on the types of plaques or tangles they were associated with. Areas of inflammation characterized by lack of P2RY12-positive microglia around mature plaques could be observed, but many diffuse plaques showed colocalization with P2RY12-positive microglia. Based on these results, P2RY12 expression by microglia should not be considered solely a marker of resting microglia as P2RY12 immunoreactivity was identifying microglia positive for CD68, progranulin and to a limited extent HLA-DR, markers of activation.

Cognitive control constrains memory attributions

2019 ◽  
Vol 42 ◽  
Author(s):  
Colleen M. Kelley ◽  
Larry L. Jacoby
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cognitive Control

Abstract Cognitive control constrains retrieval processing and so restricts what comes to mind as input to the attribution system. We review evidence that older adults, patients with Alzheimer's disease, and people with traumatic brain injury exert less cognitive control during retrieval, and so are susceptible to memory misattributions in the form of dramatic levels of false remembering.

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