Recent research on Alzheimers: Blocking an immune signaling chemical allows macrophages to clear plaques in mice
June 06, 2008
Medicine | Science

Blocking TGF-β-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology.

A new possible treatment target has been demonstrated by a group of researchers working with transgenic mice that are used to model Alzheimer's in humans. According to New Scientist:
"Richard Flavell at Yale University and colleagues created transgenic mice predisposed to develop brain plaques, and doubly transgenic mice that also had a gene that blocks TGF-beta, a chemical used by the immune system."

"The researchers expected the second set to fare worse than the first. But to their surprise, the doubly transgenic mice performed better on various mazes"...

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Posted by ellen at June 06, 2008 08:45 AM
Useful definitions:

  • The Tg2576 Alzheimer's disease mouse model: Genetically engineered to overexpress mutant human amyloid precursor protein, these mice have been shown to have memory loss correlated with the amount of detergent-insoluble Aβ aggregates. Aβ insol is a surrogate marker for small assemblies of Amyloid [proteins] that disrupt cognition and occur as intermediates during Aβ insol formation, and they are the first descriptive in vivo data supporting their role in impairing memory. They are used to model Alzheimer's disease in research.
  • Macrophages (from Wikipedia) (Greek: "big eaters", from makros "large" + phagein "eat") (mø[1]) are cells within the tissues that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes, acting in both non-specific defense (or innate immunity) as well as specific defense (or cell-mediated immunity) of vertebrate animals. Their role is to phagocytose (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen.

    A macrophage of a mouse stretching its "arms" (Pseudopodia) to engulf two particles, possibly pathogens [Obli at en.wikipedia CC-BY-SA-2.0.]

  • Glial cells, commonly called neuroglia or simply glia (Greek for "glue"), are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system. In the human brain, glia are estimated to outnumber neurons by about 10 to 1.[1]

  • Microglia are a type of glial cell that acts as the first and main form of active immune defense in the central nervous system (CNS). Microglia constitute 20% of the total glial cell population within the brain

  • Cytokine: A small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells. The cytokines includes the interleukins, lymphokines and cell signal molecules, such as tumor necrosis factor and the interferons, which trigger inflammation and respond to infections.

  • Pleiotropic cytokine: cytokine that affects the activity of multiple cell types. A cytokine is a small protein that has a specific effect on the interactions between cells, on communications between cells, or on the behavior of cells.

  • Excerpts from the article:


    Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology.
    Authors: Town,Terrence, et al.

    Source: Nature medicine, 2008, 14, 6, 681, Nature Pub. Co., New York, NY

    The short version (my words): Tg2576 mice [mice used to model Alzheimer's disease in humans] show hyperactivity probably resulting from brain injury related to their disease. The researchers genetically blocked a type of immune system signalling in the Alzheimer's mice and found that it completely mitigated the hyperactivity associated with mouse "Alzheimer's" disease and partially mitigated the memory deficits.

    From the article abstract: "Aged doubletransgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular b-amyloid deposits and Aβ abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of Aβ-containing peripheral macrophages around cerebral vessels and b-amyloid plaques."

    "TGF-βs are pleiotropic cytokines with central roles in immune suppression, immune homeostasis and repair after injury. TGF-β1 in brain dampens microglial activation. However, TGF-β1 overexpression promotes brain inflammation, simultaneously accelerates brain vascular b-amyloid deposits and reduces parenchymal β-amyloid deposits, and elicits neuronal Aβ secretion."

    "We hypothesized that blocking innate immune TGF-β signaling
    would impair cerebral Aβ clearance
    , but, as detailed below, we found
    support for the converse hypothesis

    "Tg2576 mice showed hyperactivity probably resulting from
    disinhibition associated with hippocampal or cortical injury whereas
    the Tg2576-CD11c-DNR mice showed complete hyperactivity mitigation. ..Similar results were observed during novel Y-maze exploration..."


    From the Yale Office of Public Affairs Press release:

    Researchers Clear up Alzheimer's Plaques in Mice

    "New Haven, Conn. — Blocking a common immune system response cleared up plaques associated with Alzheimer's Disease and enabled treated mice to recover some lost memory, Yale University researchers report Friday in the journal Nature Medicine.

    Researchers hope the new approach may one day overcome one of the biggest obstacles to development of new dementia medications – the difficulty in finding drugs that can safely cross the blood-brain barrier.

    The results of the research surprised the scientists working in the lab of Richard Flavell, senior author of the paper, chairman of the Department of Immunobiology at Yale and investigator with the Howard Hughes Medical Institute. Flavell's team originally thought that blocking the immune system molecule TGF-Β (or transforming growth factor), might actually increase the buildup of amyloid plaques associated with Alzheimer's Disease

    Earlier studies had shown that Alzheimer's patients tend to have elevated amounts of TGF-β, which plays a key role in activating immune system response to injury. Some had thought the presence of the molecule was simply the result of an immune response to the molecular processes that produce plaques.

    Instead, the team found that as much as 90 percent of the plaques were eliminated from the brains of mice genetically engineered to block TGF-β.

    "It was like a vacuum cleaner had removed the plaques," Flavell said...."

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