Reduced Reelin Expression Accelerates Amyloid-  Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice

Abstract

In addition to the fundamental role of the extracellular glycoprotein Reelin in neuronal development and adult synaptic plasticity, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). In vitro data revealed a biochemical link between Reelin-mediated signaling, Tau phosphorylation, and amyloid precursor protein (APP) processing. To directly address the role of Reelin in amyloid-␤ plaque and Tau pathology in vivo, we crossed heterozygous Reelin knock-out mice (reeler) with transgenic AD mice to investigate the temporal and spatial AD-like neuropathology. We demonstrate that a reduction in Reelin expression results in enhanced amyloidogenic APP processing, as indicated by the precocious production of amyloid-␤ peptides, the significant increase in number and size of amyloid-␤ plaques, as well as age-related aggravation of plaque pathology in double mutant compared with single AD mutant mice of both sexes. Numerous amyloid-␤ plaques accumulate in the hippocampal formation and neocortex of double mutants, precisely in layers with strongest Reelin expression and highest accumulation of Reelin plaques in aged wild-type mice. Moreover, concentric accumulations of phosphorylated Tau-positive neurons around amyloid-␤ plaques were evident in 15-month-old double versus single mutant mice. Silver stainings indicated the presence of neurofibrillary tangles, selectively associated with amyloid-␤ plaques and dystrophic neurites in the entorhinal cortex and hippocampus. Our findings suggest that age-related Reelin aggregation and concomitant reduction in Reelin-mediated signaling play a proximal role in synaptic dysfunction associated with amyloid-␤ deposition, sufficient to enhance Tau phosphorylation and tangle formation in the hippocampal formation in aged Reelin-deficient transgenic AD mice.

Decisive role of Reelin signaling during early stages of Alzheimer’s disease

“…In agreement with these in vitro findings, genetically reduced Reelin levels in APP swe,arc mice increased the production of Aβ peptide and significantly aggravated the plaque pathology (Kocherhans et al, 2010). Moreover, Reelin reduction in these mice, expressing endogenous mouse Tau protein, induced the formation of PHF-like accumulations in the vicinity of the plaques (Kocherhans et al, 2010).…”

“…While its expression during brain development is largely restricted to CajalRetzius cells in the marginal zone, Reelin expression in the adult brain is confined to olfactory and limbic pathways (Fig. 1C), where it modulates spine dynamics and synaptic plasticity, as well as suppresses Tau hyperphosphorylation (Herz and Chen, 2006, Forster et al, 2010, Knuesel, 2010. As documented previously (Alcantara et al, 1998, Martinez-Cerdeno et al, 2002, Ramos-Moreno et al, 2006, Reelin is expressed by granule, mitral and tufted cells of the olfactory bulb.…”

“…Moreover, Reelin reduction in these mice, expressing endogenous mouse Tau protein, induced the formation of PHF-like accumulations in the vicinity of the plaques (Kocherhans et al, 2010).…”

“…3D electron microscopy in mice revealed that these protein accumulations are of intracellular origin (Doehner et al, 2012), strikingly resembling 3D reconstruction of the axonal diverticula in aged rhesus monkeys (Fiala et al, 2007). These bud-off granules are engulfed by surrounding glia (Knuesel et al, 2009, Madhusudan et al, 2009, Doehner et al, 2012, and were shown to be positive for various intracellular proteins including APP/Aβ and Tau (Doehner et al, 2010). In AD-transgenic and in prenatally challenged wild-type mice, the number and size of these granules is increased and are enriched with degenerative mitochondria and other organelles (Knuesel et al, 2009, Doehner et al, 2012.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Importantly, ApoE4 strongly interferes with these synapse-enhancing functions of Reelin by sequestering ApoE receptors in intracellular compartments (Chen et al 2010) (Fig. 3), thus providing a novel mechanism by which accelerated spine loss, increased tau phosphorylation (Kocherhans et al 2010), loss of network homeostasis Palop and Mucke 2010), and earlier disease onset through loss of neuroprotective compensatory bandwidth (Korwek et al 2009) can be readily explained. This mechanism is also consistent with the finding that ApoE4 reduces spine density and dendritic complexity in cortical neurons in vivo (Dumanis et al 2009).…”