Alzheimer's amyloid-β and tau protein accumulation is associated with decreased expression of the LDL receptor-associated protein in human brain tissue.

Glenda M Halliday,Anita Y Bahar,Claire E Shepherd,Andrew J Affleck,Francine Carew‐Jones,David H Small,Gillian Gregory

doi:10.1002/brb3.1672

Abstract

IntroductionOne of the major neuropathological features of Alzheimer's disease (AD) is the accumulation of amyloid‐β (Aβ) protein in the brain. Evidence suggests that the low‐density lipoprotein receptor‐associated protein (RAP) binds strongly to Aβ and enhances its cellular uptake and that decreased RAP expression correlates with increased Aβ production in animal models of AD.MethodsThe current study examined whether RAP levels change in AD human brain tissue and whether they are related to the amount of AD pathology. RAP and NeuN levels were determined by Western blot, while low‐density lipoprotein receptor‐related protein 1 (LRP1), tau and Aβ levels were determined by ELISA in the temporal cortex of 17 AD and 16 control cases.ResultsAn increase in total Aβ and insoluble and soluble tau protein was observed in AD brain tissue. In contrast, RAP levels were significantly decreased in AD brain tissue compared to controls. Correlation analysis revealed that levels of RAP correlated with both total Aβ and soluble and insoluble tau levels. Neither LRP1 nor NeuN levels were significantly altered in AD brain tissue homogenates and did not correlate with Aβ or tau protein levels.ConclusionReduction in RAP may contribute to the accumulation and aggregation of Aβ in the AD brain.

Highlights

One of the major neuropathological features of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) protein in the brain
Our preliminary studies showed that NeuN, receptor-associated protein (RAP), and lipoprotein receptor-related protein 1 (LRP1) were located in the SDS fraction, so protein levels were analyzed in these fractions
We show significantly reduced levels of RAP in AD brain tissue

Summary

| METHODS

Fresh-frozen brain tissue from the inferior temporal cortex was provided from the Sydney Brain Bank for 33 cases, including 17 AD and 16 pathological and disease-free controls, (Table 1). Crude protein extracts were prepared from 200 mg of frozen human brain tissue taken from the inferior temporal cortex for analysis of Aβ (Tris-buffered saline (TBS) soluble, sodium dodecyl sulfate (SDS) soluble and formic acid soluble), NeuN (SDS soluble), RAP (SDS soluble), and LRP1 (SDS soluble). The pellet was resuspended in paired helical fraction (PHF) extraction buffer (10 mM Tris, 10% sucrose, 0.85 M NaCl, 1 mM EGTA, pH 7.4) and centrifuged at 15,000 g for 20 minutes at 4°C. Alzheimer's disease cases had significantly lower RAP levels compared to controls (p < .0001, Figure 1a) no significant differences in the brain tissue levels of LRP1 (p = .45, Figure 1c) or NeuN (p = .59, Figure 1b) were seen between groups (Figure 1, Table 2).

| DISCUSSION

Findings

| CONCLUSION