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

Abstract

Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. AbstractAlzheimer`s disease (AD) is one of the largest unmet medical needs of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles (NFTs), the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiology characteristic of late-onset AD.3

Reelin immunoreactivity in neuritic varicosities in the human hippocampal formation of non-demented subjects and Alzheimer’s disease patients

“…Based on recent experimental evidence demonstrating that multiple exposures to viral-like immune challenges are sufficient to induce AD-like neuropathology in aged wild-type mice [8], we were able to identify a crucial trigger and to reconstruct the temporal-spatial sequence of pathophysiological changes that characterize the earliest disease stages. The integration of experimental data of the last three decades enabled us to substantiate and expand our findings to propose a cellular mechanism of the neuropathological changes and its progression across interconnected brain areas that characterize sporadic AD [9,10]. The new hypothesis highlights the detrimental effect of chronic inflammatory conditions on basic cellular functions in long-projection neurons of the olfactory-limbic system during aging.…”

Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease

“…However, the contribution of Reelin to AD pathogenesis and progression is not yet understood 36 . Here we addressed the relationships between Reelin and Ab aggregation and show that, both in vitro and in vivo, Reelin modifies the kinetics of Ab 42 aggregation, delaying amyloid fibril formation.…”

Genes associated with the progression of neurofibrillary tangles in Alzheimer’s disease

“…Genes related to the phosphorylation and dephosphorylation of tau, such as GSK3B and PPP1CA , 19,20 did not show significant association with Braak NFT stage here. Concerning three genes, RELN 21,22 , PTGS2 23,24 and DCHS2 25 , there have been reports mentioning their involvment in AD. Three proteins, RELN, PTGS2 and DCHS2, directly interact with COPS5 (Figure 3), which directly interacts with APP and thus increases Aβ production.…”