Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Darstellung von Mikrogliaaktivierung und Glukoseverbrauch in einem Maus Modell für Morbus Alzheimer

In Alzheimer´s disease (AD), persistent microglial activation as sign of chronic neuroinflammation contributes to disease progression. Our study aimed to in vivo visualize and quantify microglial activation in 13- to 15-month-old AD mice using [11C]-(R)-PK11195 and positron emission tomography (PET). We attempted to modulate neuroinflammation by subjecting the animals to an anti-inflammatory treatment with pioglitazone (5-weeks’ treatment, 5-week wash-out period). [11C]-(R)-PK11195 distribution volume values in AD mice were significantly higher compared with control mice after the wash-out period at 15 months, which was supported by immunohistochemistry data. However, [11C]-(R)-PK11195 μPET could not demonstrate genotype- or treatment-dependent differences in the 13- to 14 month-old animals, suggesting that microglial activation in AD mice at this age and disease stage is too mild to be detected by this imaging method.Im Verlauf des Morbus Alzheimer unterhält eine persistierende Aktivierung der Mikroglia als Ausdruck einer chronischen Entzündung wesentlich das Voranschreiten dieser Erkrankung. Ziel unserer Untersuchung war die nicht-invasive Darstellung und Quantifizierung von Mikroglia-Aktivität im Gehirn von 13- bis 15-Monate alten Alzheimer-Mäusen mittels [11C]-(R)-PK11195 und Positronen-Emissions-Tomographie (PET). Weiterhin versuchten wir durch eine anti-inflammatorische Behandlung mit dem Wirkstoff Pioglitazon (5 Wochen Therapie, 5 Wochen Auswasch-Phase) die Neuro-Inflammation zu modulieren. Nach der Auswasch-Phase war das [11C]-(R)-PK11195 Verteilungsvolumen in 15-Monate alte Alzheimertieren signifikant höher als in Kontrolltieren. Dieses Ergebnis konnte auch immunhistochemisch bestätigt werden. [11C]-(R)-PK11195 μPET konnte aber keine genotypischen oder durch die Behandlung bedingten Unterschiede in den 13- oder 14-Monate alten Tieren darstellen. Diese Ergebnissen legen nahe, daß die Mikroglia-Aktivität in Alzheimermäusen dieses Alters und Krankheitsstadiums zu schwach ist, um mit dieser Bildgebungsmethode detektiert werden zu können