Deciphering neurodegeneration: Inflammation, immune response, and Alzheimer's

Participating Experts: Beth Stevens, PhD (Children's Hospital Boston) and Todd E. Golde, MD PhD (U. Florida)
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Download the TREM2 signaling pathway diagram: https://cst-science.com/yyluqj

There is growing recognition that the nervous and immune systems interact under both healthy and diseased conditions. This offers an excellent opportunity to define the role and molecular characteristics of neuroinflammation in neurodegenerative disorders. Chronic activation of the innate immune system is now well established as an underlying factor contributing to neurodegeneration—the progressive dysfunction and loss of neurons in the central nervous system leading to cognitive and motor disorders such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and others. Microglia, the primary immune cells of the brain, are critical in the maintenance of brain homeostasis, but lose their functionality during the course of aging and neurodegenerative diseases. While the majority of innate immune responses to disease stressors are mediated by the microglia, perivascular macrophages and peripheral myeloid cell populations can also gain access to the diseased brain and participate in neuroinflammatory signaling. Thus, a better understanding of how immune responses regulate neuronal homeostasis, and of the circumstances leading to dysregulation in pathological conditions, is essential to developing effective therapies and mitigating disease impact. In this recorded webinar, speakers share their research on immune response–mediated onset of neurodegenerative diseases, and explain the genetic and physiological regulation of microglial function in both healthy and diseased states.

Table of Contents:
0:35 Welcome and overview
2:57 Beth Stevens speaker profile
3:57 Immune cells that re-wire the brain
4:58 Synapse loss: the strongest correlate of cognitive decline in Alzheimer’s disease
6:12 Synapse loss during development
7:57 How are synapses eliminated in health and disease?
10:00 Microglia survey the healthy brain
14:29 How do microglia know which synapses to prune?
17:22 Immune system: Complement “tag” bacteria – and synapses – for elimination
21:43 Human genetics implicate microglia in Alzheimer’s Disease
23:42 Microglia drive synapse loss and cognitive impairment in AD models
25:04 Blocking C1q complement mediated pruning pathway reduces synapse loss in disease models
26:32 The challenge: microglia have diverse roles in disease
27:25 Identifiying microglia functional states in health and disease
29:21 Summary and outlook
30:34 Todd Golde speaker profile
31:20 Can we harness innate immunity to treat Alzheimer’s and other neurodegenerative diseases?
32:36 Activated microglia in the amyloid plaque
33:57 Alzheimer’s is a complex proteinopathy
35:45 Why innate immunity? Amyloid, oligomer or virus?
39:12 Immunoproteostasis and neurodegeneration
41:07 Innate immune signals can drive selective neurodegeneration
41:57 Pro-inflammatory cytokines decrease A deposition; anti-inflammatory cytokines increase A deposition
43:25 The innate immune system is a well validated, but not well-defined target
44:36 The “Goldelocks” principle and immunoproteostasis in AD
47:00 PLCG2 and innate immunity
47:53 Can we harness immunoproteostasis to treat AD and other neurodegenerative diseases? Opportunities and challenges.
50:23 Questions and answers