Reelin immunoreactivity in neuritic varicosities in the human hippocampal formation of non-demented subjects and Alzheimer’s disease patients

Tina Notter,Irene Knuesel

doi:10.1186/2051-5960-1-27

Abstract

BackgroundReelin and its downstream signaling members are important modulators of actin and microtubule cytoskeleton dynamics, a fundamental prerequisite for proper neurodevelopment and adult neuronal functions. Reductions in Reelin levels have been suggested to contribute to Alzheimer’s disease (AD) pathophysiology. We have previously reported an age-related reduction in Reelin levels and its accumulation in neuritic varicosities along the olfactory-limbic tracts, which correlated with cognitive impairments in aged mice. Here, we aimed to investigate whether a similar Reelin-associated neuropathology is observed in the aged human hippocampus and whether it correlated with dementia status.ResultsOur immunohistochemical stainings revealed the presence of N- and C-terminus-containing Reelin fragments in corpora amylacea (CAm), aging-associated spherical deposits. The density of these deposits was increased in the molecular layer of the subiculum of AD compared to non-demented individuals. Despite the limitation of a small sample size, our evaluation of several neuronal and glial markers indicates that the presence of Reelin in CAm might be related to aging-associated impairments in neuronal transport leading to accumulation of organelles and protein metabolites in neuritic varicosities, as previously suggested by the findings and discussions in rodents and primates.ConclusionsOur results indicate that aging- and disease-associated changes in Reelin levels and proteolytic processing might play a role in the formation of CAm by altering cytoskeletal dynamics. However, its presence may also be an indicator of a degenerative state of neuritic compartments.

Highlights

Reelin and its downstream signaling members are important modulators of actin and microtubule cytoskeleton dynamics, a fundamental prerequisite for proper neurodevelopment and adult neuronal functions
We detected spherical Reelin-positive structures varying in their size from approximately 60 up to 250 μm2 predominantly located in fiber-rich structures (Figure 1 and Additional file 1: Figure S1) in both groups of subjects
Fewer deposits were detected in layer I of the entorhinal cortex (EC) and the stratum lacunosum moleculare (SLM) of the hippocampus

Summary

Introduction

Reelin and its downstream signaling members are important modulators of actin and microtubule cytoskeleton dynamics, a fundamental prerequisite for proper neurodevelopment and adult neuronal functions. Reelin accumulates within neuritic varicosities in both rodents and non-human primates [28,30], possibly related to the aging associated decrease in Reelin signaling and its protective modulation of cytoskeleton dynamics [10]. In agreement with these experimental data, recent genome wide association studies performed in elderly, non-demented individuals identified three single nucleotide polymorphisms (SNPs) in the Reelin gene that significantly correlated with increased Tau phosphorylation and concomitant appearance of neurofibrillary tangles (NFTs) [31]. Alterations in Reelin glycosylation, its proteolytic cleavage and degradation, as well as changes in its mRNA stability were shown to be changed in brain homogenates of AD patients [35,36], further highlighting the importance of proper Reelin signaling during aging

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