Accumulation of reelin‐positive plaques is accompanied by a decline in basal forebrain projection neurons during normal aging

Abstract

Besides its critical role during neurodevelopment, the extracellular glycoprotein reelin is also a pivotal regulator of adult synaptic function and plasticity, and altered reelin-mediated signalling has been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease. We have recently discovered, in aged rodents and non-human primates, a pronounced decline in reelin-positive interneurons and concomitant accumulation of reelin in extracellular amyloid-like deposits, both being associated with episodic-like memory impairments. Here, we report that these age-related neuropathological changes in hippocampus, entorhinal and piriform cortices of aged wild-type mice are accompanied by abnormal axonal varicosities and altered expression profiles of calcium-binding proteins in plaque-dense areas, as well as a significant reduction in the number of parvalbumin-positive gamma-aminobutyric acid (GABA)ergic projection neurons in basal forebrain areas, including medial septum (MS), ventral and horizontal diagonal Band of Broca (VDB/HDB) and substantia innominata (SI), compared with young subjects. In addition, a significant reduction in the number of choline acetyltransferase-positive cholinergic projection neurons was evident in the HDB/SI area but not in the MS of aged compared with young wild-type mice. No reelin-deposits were found in these basal forebrain regions. Our findings suggest that the elevated reelin plaque load in the projection areas of afferent subcortical GABAergic and cholinergic neurons including hippocampus, entorhinal and piriform cortices affects the axonal integrity and survival of these neurons, potentially contributing to the cognitive impairments observed in aged wild-type mice.

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

“…Further, Reelin is produced by the pyramidal cells of the piriform and entorhinal cortex projecting to thalamus and hippocampus, respectively. In the hippocampus itself, Reelin expression is restricted to local interneurons (Alcantara et al, 1998, Koliatsos et al, 2004, Ramos-Moreno et al, 2006, Knuesel et al, 2009. Finally, Reelin is also expressed in the corticomedial amygdaloid nuclei and the paraventricular nuclei of the thalamus.…”

“…It would be highly relevant, therefore, to check in the adult brain if oligodendrocytes, which express Reelin in vitro (Siebert and Osterhout, 2011) Importantly, we were recently able to demonstrate that a viral-like prenatal immune challenge predisposes the offspring to develop an AD-like phenotype, which is induced if the challenge is repeated for a second time during adulthood (Krstic et al, 2012a). In these prenatally challenged mice, the loss of Reelin expressing cells (Meyer et al, 2008, Knuesel et al, 2009 coincided with an increase in APP production and cleavage, Tau hyperphosphorylation and missorting, as well as cognitive deficits (Krstic et al, 2012a). This is in agreement with the observations of cognitive decline in aged rats correlating with reduced Reelin expression in the entorhinal cortex (Stranahan et al, 2011a), recently confirmed by the findings of impaired spatial memory following experimental interference with Reelin signaling in the same area (Stranahan et al, 2011b).…”

“…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.…”

“…Intriguingly, Reelin was shown to accumulate in the projection areas of Reelin expressing cells in an age-dependent manner, a phenomenon observed in various species including primates (Knuesel et al, 2009). 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).…”

“…This is then followed by the integration of recent experimental findings addressing the role of the extracellular signaling protein Reelin that is selectively expressed along the affected circuits and shown to be a potent suppressor of Tau phosphorylation Chen, 2006, Knuesel, 2010). Moreover, the decline in Reelin expression is not only strongly affected by aging and chronic inflammatory conditions in animals (Knuesel et al, 2009), but constitutes also a very early phenomenon of AD pathophysiology in humans (Herring et al, 2012a). Based on the presented evidence we propose that reduction of Reelin-mediated signaling in the olfactory and limbic system accelerates and aggravates the age-associated hyperphosphorylation of Tau (Braak et al, 2011).…”