Reelin Depletion is an Early Phenomenon of Alzheimer's Pathology

Abstract

Alterations in the expression of Reelin (RELN) have been implicated in the pathology of Alzheimer's disease (AD). However, whether these changes are cause or consequence of AD remains to be resolved. To better understand the role of RELN pathway in the development of AD, we examined the expression profile of RELN and its downstream signaling members APOER2, VLDLR, and DAB1 in AD-vulnerable regions of transgenic and wildtype mice as well as in AD patients and controls across disease stages and/or aging. We show that both AD pathology and aging are associated with perturbation of the RELN pathway in a species-, region-, and molecule-specific manner. Further, we show that depletion of RELN, but not its downstream signaling molecules, is detectable long before the onset of amyloid-β pathology in the murine hippocampus and in a pre-clinical AD stage in the human frontal cortex. This early event hints at a possible causative role of RELN decline in the precipitation of AD pathology and supports RELN's potential as a pre-clinical marker for AD.

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

“…In comparison to AD susceptible brain areas, there were no alterations in NMDARs subunit expression in cerebellum of AD patients (Bi and Sze, 2002). Conversely, other studies evidenced that mRNA levels of GluN1 (Bi Additionally to a decrease in mRNA levels, the decrease in GluN2B and GluN2A subunits could be due also to a decrease in reelin levels, a protein that mediates NMDAR activity, and which is depleted in AD brains (Herring et al, 2012). On the other hand, the decrease in NMDAR subunits may also be due to an increase in STEP 61 , which contributes to the endocytosis of GluN1/GluN2B and GluN1/GluN2A receptors (Snyder et al, 2005;Kurup et al, 2010).…”

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

“…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).…”

“…1C) Here (Fig. 2), we propose that reduction of Reelin (Chin et al, 2007, Herring et al, 2012a, as a consequence of cumulative environmental injuries to the olfactory pathway (Okuyama-Yamamoto et al, 2005) or injury/disease/infection-induced chronic inflammation (Knuesel et al, 2009, Krstic andKnuesel, 2013), accelerates the age-dependent phosphorylation of Tau and instability of interneuronal connections. This will in turn result in a more pronounced synaptic loss and wide-spread formation of NFTs, a correlate of disease progression and dementia severity in patients with AD.…”

“…Finally, in humans both loss of Reelin expressing cells in the entorhinal cortex (Baloyannis, 2005, Chin et al, 2007 and drastically reduced levels of Reelin protein in the hippocampus, entorhinal and frontal cortex (Herring et al, 2012a) ), reflecting either a potentially compensatory mechanism or an effect of advanced disease processes. Unfortunately, as a likely consequence of the high inter-subject variability, the relative concentrations of Reelin and its proteolytic fragments in brain and CSF of AD patients and non-demented controls are inconclusive (Ignatova et al, 2004, Botella-Lopez et al, 2006, Notter and Knuesel, unpublished observations).…”

The Amyloidogenic Pathway Meets the Reelin Signaling Cascade: A Cytoskeleton Bridge Between Neurodevelopment and Neurodegeneration

“…Accordingly, Reelin expression is also decreased in brains of patients at the presymptomatic stages of AD. The progression of the disease causes in both cases, potentiate the Reelin deficiency from the hippocampus to the entorhinal cortex in mice and from the frontal cortex to the hippocampus and entorhinal cortex in humans [50,98]. The decrease in Reelin expression is linked to a reduction in CR cells at the cortical layer I in AD brains [61].…”