Mikroglia bei Alzheimer-Demenz

J. Wiltfang

doi:10.1055/s-0038-1627748

Nervenheilkunde, Table of Contents

Nervenheilkunde 2014; 33(11): 797-804
DOI: 10.1055/s-0038-1627748

Mikroglia

Schattauer GmbH

Mikroglia bei Alzheimer-Demenz

Bedeutung für Krankheitsprogression und innovative TherapieansätzeMicroglia in Alzheimer’s dementia

J. Wiltfang

¹Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Göttingen (UMG)

› Author Affiliations

Abstract

Zusammenfassung

Die Rolle der Mikroglia innerhalb der Pathophysiologie der Alzheimer-Demenz wurde deutlich unterschätzt. Das wird durch zahlreiche In-vitro- und In-vivo-Befunde belegt. Maßgebliche neue Impulse hat dieses Forschungsfeld besonders von neueren methodischen Entwicklungen, wie der Multiphoton- in-vivo-Bildgebung und Fortschritten in neuronal-mikroglialen Modellen der Cokultur erhalten. Gleichzeitig zeichnet sich ab, dass die Mikroglia eher entscheidend die Dynamik der Krankheitsprogression steuert, als dass sie primär ätiopathogenetische Bedeutung hat. Dabei zeichnet sich zunehmend ab, dass der komplexe Beitrag der Mikroglia eher einer umgekehrten U-Funktion entspricht, wie bereits für Zytokine gut belegt: Unterfunktion mit reduzierter „Clearance” von aggregierten beta-Amyloidpeptiden und verminderter Synthese neurotropher Faktoren könnte vergleichbar schädlich sein wie Überstimulation mit erhöhter Freisetzung pro-inflammatorischer Zytokine, endoplasmatischer Stressfaktoren und reaktiver Sauerstoffradikale. Mit Blick auf potenzielle therapeutische Ansatzpunkte erscheint die pharmakologische Modulation mikroglialer Rezeptoren, wie FcgammaRIIb, Scara-1, CD33, CD36, RAGE, BECLIN- 1 und TREM2, sowie der NLRP-3-abhängigen inflammatorischen Signalkaskade besonders erfolgversprechend. In diesem Zusammenhang zeichnen sich auch attraktive Kombinationstherapien ab, einerseits in der Modulation synergistisch wirkender mikroglialer Rezeptoren, andererseits in der Kombination mit den bisher eher enttäuschenden beta-Amyloid- Immunisierungsstrategien. Im Zusammenhang mit Befunden zur altersabhängig eingeschränkten protektiven Funktion residenter Mikroglia bei AD (microglial senescence) wird auch der Einsatz von Strategien der Knochenmarktransplantation mit Invasion knochenmarkstämmiger Mikrogliazellen (BMDM, bone marrow-derived microglia) in das ZNS diskutiert. Diese Therapieansätze sind zurzeit voraussichtlich therapeutisch weniger gut steuerbar und bei Alzheimerdemenz deutlich weiter von ersten klinischen Studien entfernt.

Summary

The role of microglia in the pathophysiology of Alzheimer’s disease has been significantly underestimated. This is supported by numerous in vitro and in vivo findings. Significant new impulses received this research field especially of newer methodological developments, such as the multi-photon in vivo imaging and advances in neuronal – microglial co-culture models. It is only now becoming apparent that the microglia rather influences the dynamics of disease progression than being of primarily etiopathogenic significance. We begin to understand that the complex contribution of microglia is more like an inverted U – function, as has been well documented for cytokines: Subfunction with reduced clearance of aggregated beta – amyloid peptides and reduced synthesis of neurotrophic factors could be comparable harmful as hyperstimulation with increased release of pro-inflammatory cytokines, endoplasmatic stress factors and reactive oxygen radicals. With regard to potential therapeutic targets currently the pharmacological modulation of microglial receptors, such as Fcgammma RIIb, Scara-1, CD33, CD36, RAGE, Beclin-1, TREM2, and NLR-3 dependent inflammatory signalling cascade appears particularly promising. In this context, also attractive combination therapies are emerging, e.g. the modulation of synergistic microglial receptors, or, in combination with the previously rather disappointing beta – amyloid immunization strategies. Due to new results on age-dependent limited protective function of resident microglia in AD (microglial senescence) the use of strategies for bone marrow transplantation with invasion of bone marrow-derived microglia into the CNS is being discussed. Currently all these therapeutic approaches seem to be not suitable for therapy and therefore not qualified for first clinical trials in Alzheimer’s disease.

Schlüsselwörter

Mikroglia - Alzheimer-Demenz - Krankheitsprogression - Therapie

Keywords

Microglia - Alzheimer’s dementia - disease progression - therapy

Full Text

References

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