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Genetics ignite focus on microglial inflammation in Alzheimer's disease.

Malik M, Parikh I, Vasquez JB, Smith C, Tai L, Bu G, LaDu MJ, Fardo DW, Rebeck GW, Estus S - Mol Neurodegener (2015)

Bottom Line: Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function.In this review, we discuss interpretation of genetic studies.  We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE.We then present a model for how these factors may interact to modulate microglial function in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St, Lexington, KY, 40536, USA. manasi.malik@uky.edu.

ABSTRACT
In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies.  We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD.

No MeSH data available.


Related in: MedlinePlus

Microglial activation can be neuroprotective and/or neurotoxic; the actions of AD risk proteins modulate these effects. The normal actions of CD33 and SHIP1 (encoded by INPP5D) appear to antagonize both forms of microglial activation, while CR1 action appears to promote both Aβ phagocytosis and the production of neurotoxic pro-inflammatory cytokines such as TNF. TREM2 appears to promote phagocytosis while dampening pro-inflammatory cytokine production. ABCA7 helps to mediate phagocytosis. APOE2 and APOE3 are anti-inflammatory, while APOE4 promotes inflammation and neurotoxicity
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Fig2: Microglial activation can be neuroprotective and/or neurotoxic; the actions of AD risk proteins modulate these effects. The normal actions of CD33 and SHIP1 (encoded by INPP5D) appear to antagonize both forms of microglial activation, while CR1 action appears to promote both Aβ phagocytosis and the production of neurotoxic pro-inflammatory cytokines such as TNF. TREM2 appears to promote phagocytosis while dampening pro-inflammatory cytokine production. ABCA7 helps to mediate phagocytosis. APOE2 and APOE3 are anti-inflammatory, while APOE4 promotes inflammation and neurotoxicity

Mentions: In aggregate, we propose that microglial activation state reflects a homeostatic balance between proteins like CD33 and SHIP1 that inhibit all microglial activation, proteins like TREM2 that promote phagocytic activity without inflammatory cytokines, and proteins like CR1 that are non-specific immune activators. We would also group apoE4 in the last category, relative to the immunosuppressive activities of apoE3 and, progressively, apoE2 (Fig. 2).Fig. 2


Genetics ignite focus on microglial inflammation in Alzheimer's disease.

Malik M, Parikh I, Vasquez JB, Smith C, Tai L, Bu G, LaDu MJ, Fardo DW, Rebeck GW, Estus S - Mol Neurodegener (2015)

Microglial activation can be neuroprotective and/or neurotoxic; the actions of AD risk proteins modulate these effects. The normal actions of CD33 and SHIP1 (encoded by INPP5D) appear to antagonize both forms of microglial activation, while CR1 action appears to promote both Aβ phagocytosis and the production of neurotoxic pro-inflammatory cytokines such as TNF. TREM2 appears to promote phagocytosis while dampening pro-inflammatory cytokine production. ABCA7 helps to mediate phagocytosis. APOE2 and APOE3 are anti-inflammatory, while APOE4 promotes inflammation and neurotoxicity
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4595327&req=5

Fig2: Microglial activation can be neuroprotective and/or neurotoxic; the actions of AD risk proteins modulate these effects. The normal actions of CD33 and SHIP1 (encoded by INPP5D) appear to antagonize both forms of microglial activation, while CR1 action appears to promote both Aβ phagocytosis and the production of neurotoxic pro-inflammatory cytokines such as TNF. TREM2 appears to promote phagocytosis while dampening pro-inflammatory cytokine production. ABCA7 helps to mediate phagocytosis. APOE2 and APOE3 are anti-inflammatory, while APOE4 promotes inflammation and neurotoxicity
Mentions: In aggregate, we propose that microglial activation state reflects a homeostatic balance between proteins like CD33 and SHIP1 that inhibit all microglial activation, proteins like TREM2 that promote phagocytic activity without inflammatory cytokines, and proteins like CR1 that are non-specific immune activators. We would also group apoE4 in the last category, relative to the immunosuppressive activities of apoE3 and, progressively, apoE2 (Fig. 2).Fig. 2

Bottom Line: Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function.In this review, we discuss interpretation of genetic studies.  We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE.We then present a model for how these factors may interact to modulate microglial function in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St, Lexington, KY, 40536, USA. manasi.malik@uky.edu.

ABSTRACT
In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer's disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies.  We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD.

No MeSH data available.


Related in: MedlinePlus