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

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.