[P2-197]: AMYLOID DEPOSITION, TAU AGGREGATION AND MICROGLIAL ACTIVATION CORRELATE WITH VASCULAR BURDEN IN VIVO IN ALZHEIMER'S DISEASE

AbstractMicroglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. We assessed the effect of microglial activation in the aging human brain by calculating the proportion of activated microglia (PAM), based on morphologically defined stages of activation in four regions sampled postmortem from up to 225 elderly individuals. We found that cortical and not subcortical PAM measures were strongly associated with β-amyloid, tau-related neuropathology, and rates of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ɛ4, the strongest genetic risk factor for Alzheimer’s disease. Mediation modeling suggests that PAM accelerates accumulation of tau pathology leading to cognitive decline, supporting an upstream role for microglial activation in Alzheimer’s disease. Genome-wide analyses identified a common variant (rs2997325) influencing cortical PAM that also affected in vivo microglial activation measured by positron emission tomography using [11C]-PBR28 in an independent cohort. Finally, we identify overlaps of PAM’s genetic architecture with those of Alzheimer’s disease, educational attainment, and several other traits.

Download Full-text

Bioavailability and Pharmaco-therapeutic Potential of Luteolin in Overcoming Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190319141835 ◽

2019 ◽

Vol 18 (5) ◽

pp. 352-365 ◽

Cited By ~ 6

Author(s):

Fahad Ali ◽

Yasir Hasan Siddique

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

In Vivo Models ◽

Naturally Occurring ◽

Current Review ◽

Tau Aggregation ◽

Dose Limiting Toxicity

Luteolin is a naturally occurring, yellow crystalline flavonoid found in numerous dietary supplements we frequently have in our meals. Studies in the last 2 decades have revealed its therapeutic potential to reduce the Alzheimer’s disease (AD) symptoms in various in vitro and in vivo models. The anti-Alzheimer’s potential of luteolin is attributed to its ability to suppress Aβ as well as tau aggregation or promote their disaggregation, down-regulate the expression of COX-2, NOS, MMP-9, TNF-α, interleukins and chemokines, reduce oxidative stress by scavenging ROS, modulate the activities of transcription factors CREB, cJun, Nrf-1, NF-κB, p38, p53, AP-1 and β-catenine and inhibiting the activities of various protein kinases. In several systems, luteolin has been described as a potent antioxidant and anti-inflammatory agent. In addition, we have also discussed about the bio-availability of the luteolin in the plasma. After being metabolized luteolin persists in plasma as glucuronides and sulphate-conjugates. Human clinical trials indicated no dose limiting toxicity when administered at a dose of 100 mg/day. Improvements in the formulations and drug delivery systems may further enhance the bioavailability and potency of luteolin. The current review describes in detail the data supporting these studies.

Download Full-text

Cerebrovascular and microglial states are not altered by functional neuroinflammatory gene variant

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15626719 ◽

2016 ◽

Vol 36 (4) ◽

pp. 819-830 ◽

Cited By ~ 3

Author(s):

Daniel Felsky ◽

Philip L De Jager ◽

Julie A Schneider ◽

Konstantinos Arfanakis ◽

Debra A Fleischman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation ◽

Protein A ◽

Translocator Protein ◽

Postmortem Brain ◽

Amyloid Angiopathy ◽

Religious Orders ◽

Binding Characteristics

The translocator protein, a microglial-expressed marker of neuroinflammation, has been implicated in Alzheimer’s disease, which is characterized by alterations in vascular and inflammatory states. A TSPO variant, rs6971, determines binding affinity of exogenous radioligands in vivo; however, the effect of these altered binding characteristics on inflammatory and cerebrovascular biomarkers has not been assessed. In 2345 living subjects (Alzheimer’s Disease Neuroimaging Initiative, n = 1330) and postmortem brain samples (Religious Orders Study and Memory and Aging Project, n = 1015), we analyzed effects of rs6971 on white matter hyperintensisites, cerebral infarcts, circulating inflammatory biomarkers, amyloid angiopathy, and microglial activation. We found that rs6971 does not alter translocator protein in a way that impacts cerebrovascular and inflammatory states known to be affected in dementia.

Download Full-text

Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease

Molecular Pharmacology ◽

10.1124/mol.111.071290 ◽

2011 ◽

Vol 79 (6) ◽

pp. 964-973 ◽

Cited By ~ 166

Author(s):

Ana María Martín-Moreno ◽

David Reigada ◽

Belén G. Ramírez ◽

R. Mechoulam ◽

Nadia Innamorato ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Microglial Activation

Download Full-text

Relationship between cortical iron and tau aggregation in Alzheimer’s disease

Brain ◽

10.1093/brain/awaa089 ◽

2020 ◽

Vol 143 (5) ◽

pp. 1341-1349 ◽

Cited By ~ 8

Author(s):

Nicola Spotorno ◽

Julio Acosta-Cabronero ◽

Erik Stomrud ◽

Björn Lampinen ◽

Olof T Strandberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Critical Role ◽

Disease Process ◽

Amyloid Β ◽

Cortical Atrophy ◽

Tau Pet ◽

Tau Aggregation ◽

The Relationship

Abstract A growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer’s disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer’s disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer’s disease aetiology.

Download Full-text