SUCLG2 as determinator of CSF Aβ1-42 levels and attenuator of cognitive decline in Alzheimer’s disease
Challenges related to the understanding of Alzheimer’s disease (AD) are the complexity of pathological pathways involved and the need to identify modulators of said pathways. Aβ1-42 and pTau181, which are markers for amyloid deposition and neurodegeneration respectively, are well established. Several factor influences levels of these biomarkers, however, their molecular identity remains unidentified.
(upper panel) Increased levels of SUCLG2 in AD ApoE 3/3 brains. Soluble extracts from postmortem frontal cortex of AD dementiapatients with ApoE 3/4 and ApoE 3/3 status plus age-matched healthy controls (CN) were probed with an antibody to SUCLG2.(lower panel) SUCLG2 silencing is detrimental to extracellularAb1–42. FAM-Ab1–42 phagocytosis was impaired inBV2cells in which SUCLG2was silenced by two distinct siRNA compared with negative control siRNA(n ¼ 6). FAM-Ab1–42 was added at a 500 nM final concentration and the amount of internalized Ab1–42 was assessed at the indicated time points, showing that cells contain less Ab1–42 in the absence of SUCLG2.
A SNP in SUCLG2 (rs62256378) was identified which not only is associated with higher Aβ1-42 levels but also with cognitive decline in AD dementia patients. However, SUCLG2 seems not to confer AD susceptibility. The SNP effect is seen after clinical AD diagnosis is made. The strongest effect was observed in the group of APOE-e4 noncarriers The inventors propose that both SUCLG2 and APOE interact in the same unknown biological pathway which affects Aβ1-42 levels. Also, the influence SUCLG2 has on Aβ1-42 was particularly high. Further studies suggest that SUCLG2 has a beneficial role in the microglial clearance of Aβ1-42 levels and in the clinical course of AD. These effects may be due to improved respiratory chain and mitochondrial DNA maintenance which enhances mitochondrial function by reducing oxidative stress and pro-inflammatory activity.
The technology is available for in-licensing and/or joint development.
A meta-analysis of 3independent genome-wide association studies was performed and top findings were replicated in an independent sample. Follow up of promising findings by specific analyses and functional experiments in vitro are in preparation.
European Patent application EP 13 196 119.5 "Means and methods for establishing a clinical prognosis of diseases associated with the formation of aggregates of Aß1-42" claiming priority was filed in December 2013.
Ramirez et al. Hum Mol Genet. 2014 Jul 15. pii: ddu372. [Epub ahead of print]