Age-related accumulation of Reelin in amyloid-like deposits

Abstract

Age-related accumulation of Reelin in amyloid-like deposits Abstract Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD. ABSTRACTAccumulating evidence suggest that alterations in Reelin-mediated signalling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits.These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Aβ species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.3

Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice

“…However, Nomura et al (1996) found no evidence of deposits or granular structures in SAMP8 brain although they reported an increase in APP-like immunoreactivity. From their description, the Aβ-LI and reelin deposits containing Aβ reported by Knuesel et al (2009) would appear to be the pathological granules that we have investigated further in the present study. Given that we found that they do not stain with Thioflavin S or with Hylite-AF488, and that Aβ-staining is a mistake due to the presence of the contaminant IgM, we conclude that there is no deposition of Aβ in these granular structures.…”

“…The deposits described have included, among others, β/A4 protein-like immunoreactivity granular structures (β-LIGS) (Takemura et al 1993), amyloid β-peptide-like immunoreactivity deposits (Aβ-LI) (Fukunari et al 1994), reelin deposits that contained Aβ (Knuesel et al 2009) and the hippocampal granules containing Aβ(1-40) and Aβ(1-42) (Del Valle et al 2010;Currais et al 2012;Porquet et al 2013;Yamaguchi et al 2012). Morley et al (2000) found Aβ plaques that were not discernible before 16 months of age and became more prevalent at 22 months of age.…”

“…In fact, they have been found to contain glycogen, glycoproteins and proteoglycans (Akiyama et al 1986;Kuo et al 1996;Manich et al 2011;Takemura et al 1993). Extracellular matrix-related proteins such as heparan sulphate proteoglycan, laminin (Jucker et al 1994;Kuo et al 1996) and reelin (Knuesel et al 2009) have been detected in C57BL/6 granules, and polyglucosans have been described as the major components of granules in the AKR strain (Mitsuno et al 1999).…”

Impact of Prenatal Immune System Disturbances on Brain Development

“…On the other hand, an in utero immune challenge at GD17 preferentially affected the expression levels of the hippocampal NR1 subunit of the NMDA receptor as compared to GD9 and control treatments, which were paralleled by impairments in working memory performance. These studies revealed also that a prenatal immune challenge during late gestation resulted in acceleration of aging, as indicated by the earlier formation of Reelin-positive extracellular amyloid-like deposits, a neuropathological feature detected in the hippocampal formation in several species that is accompanied by a reduction in Reelin-expressing neurons (Knuesel et al, 2009;Knuesel, 2010). Both neuropathological alterations significantly correlated with hippocampusdependent episodic-like memory deficits (Knuesel et al, 2009).…”

“…These studies revealed also that a prenatal immune challenge during late gestation resulted in acceleration of aging, as indicated by the earlier formation of Reelin-positive extracellular amyloid-like deposits, a neuropathological feature detected in the hippocampal formation in several species that is accompanied by a reduction in Reelin-expressing neurons (Knuesel et al, 2009;Knuesel, 2010). Both neuropathological alterations significantly correlated with hippocampusdependent episodic-like memory deficits (Knuesel et al, 2009). We found that healthy and cognitively normal subjects were able to sufficiently clear and degrade these deposits, whereas cognitively impaired aged mice failed to do so.…”