In this study, we reported that LR11 protein can be detected and measured in CSF and that levels are significantly reduced in CSF of patients with mild to moderate AD compared to age-matched controls. This reduction was confirmed in postmortem CSF autopsy-proven AD cases, but not in non-AD dementias such as LBD, multiple system atrophy (MSA) and VAD. Perhaps not surprisingly for an APP binding protein, LR11 significantly correlated with sAPPα and sAPPβ. Despite being a LDL family member that can bind ApoE, LR11 levels did not correlate with ApoE. These findings are consistent with a primary role for LR11 as a neuronal sorting protein rather than as significant CNS ApoE receptor.
While the genetic association of LR11 with LOAD remains controversial, LR11 deficits with reductions in LR11 mRNA and protein have been a consistent finding LOAD, but not early onset familial AD cases in which overproduction of Aβ42 was known to be due to presenilin or APP mutations. This suggests that LR11 loss does not occur simply secondary to pathology and might occur at very early disease stages and even prior to diagnosis. Here we found that decreased LR11 in CSF occurred at a relatively early stage (in patients with an average MMSE score of 24), and was further confirmed in autopsy-proven AD with Braak stage III–IV. Since reduced LR11 levels have been observed in a subgroup of individuals with MCI (7
), LR11 deficits in CSF might be detectable in MCI or even earlier AD stages in a subset of LOAD at risk patients Combining LR11’s essential function in trafficking APP and regulating Aβ production, these data strongly suggest that CSF LR11s might be a useful biomarker for LOAD.
LR11 contains a vacuolar protein sorting 10 protein domain (vps10p) involved in protein transport between the plasma membrane, endosomes and late Golgi compartments (33
). Increased LR11 significantly alters the sorting and trafficking of APP to the recycling Golgi and early endosomal compartments which results in a decrease in Aβ production via the amyloidogenic pathway (1
). In addition, it has been reported that LR11 also sorts APP to intracellular protein complexes (retromers) that traffic APP away from α and β secretase (38
). Retromer trafficking dysfunction can lead to increased APP in the late endosome, an organelle where BACE activity and Aβ production are maximized (40
). Reductions of sAPP (including α-and β-sAPP) in CSF of AD patients have been reported and initially proposed as a diagnostic marker for AD (29
). However, sAPP deficits have not been widely studied or used as diagnostic markers in the clinic. In this study, sAPP, including sAPPα and sAPPβ were reduced in the CSF of AD patients. Notably, LR11 levels significantly correlated with those of sAPP. It is possible that this correlation occurs as a result of the binding of LR11 with APP and regulation of its processing. These results might provide one potential explanation for the sAPP changes in the CSF of AD patients.
Considering that LR11 is a member of the ApoE receptor family, LR11 could be influenced by ApoE in CSF and vice versa. However, ApoE levels in CSF did not differ between AD and controls, and also didn’t correlate with LR11 levels. Any role for LR11 in CNS ApoE metabolism remains hypothetical.
In summary, this study demonstrates that soluble LR11 is significantly reduced in CSF of early AD patients, and correlated with reductions in sAPP, but not ApoE. Reduced LR11 in CSF was confirmed in autopsy- proven AD cases with B
raak stage III–IV, but not in non-AD dementias such as LBD, MSA and VAD. LR11 mRNA is down-regulated in lymphoblasts and protein levels are reduced in cortical and hippocampal neurons from LOAD but not FAD patients (4
). This suggests that LR11s protein deficits might be detectable in plasma, but our attempts to measure plasma LR11 failed and any relationship with more accessible blood mRNA levels needs to be explored. Taken together, this study provides preliminary evidence that LR11 might be a potential CSF biomarker for sporadic but not familial AD. In our sample, Aβ42 was the best single CSF predictor of AD. Adding LR11 to a discriminant function with Aβ42 did improve sensitivity and specificity (AUC changes from 0.789 to 0.865, p
= 0.011), while adding T-tau or P-tau did not. These are preliminary results and without a validation sample. Since LR11 expression is sensitive to dietary omega-3 fatty acids (16
), it is not surprising that LR11 is not as closely connected to diagnosis as CSF Aβ42.
The stability of LR11 in CSF suggests that it may be used to monitor therapeutic effects of AD treatment. This would be particularly true in the case of drugs expected to work by modulating CNS LR11 expression, such as the omega-3 fatty acid, docosahexaenoic acid (16
). Due to the limited non-AD dementia sample size used here, CSF LR11’s potential as a diagnostic marker for AD should be further investigated and combined with other biomarkers with both larger sample sets including MCI or pre-clinical cases. For example, it is possible that measuring LR11 in MCI alone or in combination with Aβ would help to predict which patients with MCI are at highest risk for progression to AD.