Abstract
The neuronal Ca2+-sensor (NCS) proteins VILIP-1 and VILIP-3 have been implicated in the etiology of Alzheimer's disease (AD). Genome-wide association studies (GWAS) show association of genetic variants of VILIP-1 (VSNL1) and VILIP-3 (HPCAL1) with AD+P (+psychosis) and late onset AD (LOAD), respectively. In AD brains the expression of VILIP-1 and VILIP-3 protein and mRNA is down-regulated in cortical and limbic areas. In the hippocampus, for instance, reduced VILIP-1 mRNA levels correlate with the content of neurofibrillary tangles (NFT) and amyloid plaques, the pathological characteristics of AD, and with the mini mental state exam (MMSE), a test for cognitive impairment. More recently, VILIP-1 was evaluated as a cerebrospinal fluid (CSF) biomarker and a prognostic marker for cognitive decline in AD. In CSF increased VILIP-1 levels correlate with levels of Aβ, tau, ApoE4, and reduced MMSE scores. These findings tie in with previous results showing that VILIP-1 is involved in pathological mechanisms of altered Ca2+-homeostasis leading to neuronal loss. In PC12 cells, depending on co-expression with the neuroprotective Ca2+-buffer calbindin D28K, VILIP-1 enhanced tau phosphorylation and cell death. On the other hand, VILIP-1 affects processes, such as cyclic nucleotide signaling and dendritic growth, as well as nicotinergic modulation of neuronal network activity, both of which regulate synaptic plasticity and cognition. Similar to VILIP-1, its interaction partner α4β2 nicotinic acetylcholine receptor (nAChR) is severely reduced in AD, causing severe cognitive deficits. Comparatively little is known about VILIP-3, but its interaction with cytochrome b5, which is part of an antioxidative system impaired in AD, hint toward a role in neuroprotection. A current hypothesis is that the reduced expression of visinin-like protein (VSNLs) in AD is caused by selective vulnerability of subpopulations of neurons, leading to the death of these VILIP-1-expressing neurons, explaining its increased CSF levels. While the Ca2+-sensor appears to be a good biomarker for the detrimental effects of Aβ in AD, its early, possibly Aβ-induced, down-regulation of expression may additionally attenuate neuronal signal pathways regulating the functions of dendrites and neuroplasticity, and as a consequence, this may contribute to cognitive decline in early AD.
Highlights
In the old scriptures it is said: neither do men put new wine into old bottles, else the bottles break, and the wine runneth out, and the bottles perish, but they put new wine into new bottles, and both are preserved (Matthew 9:17)
Recent findings on the implication of neuronal Ca2+-sensor (NCS) proteins in the etiology of Alzheimer’s disease (AD), the role of VILIP-1 as cerebrospinal fluid (CSF) biomarker for AD, its correlation with mini mental state exam (MMSE) scores and predictive value for cognitive decline in healthy individuals (Lee et al, 2008; Craig-Schapiro et al, 2009; Tarawneh et al, 2011), provoke new questions about what role these Ca2+-sensors play in early cognitive impairment in AD
In this review I will focus on two members of the visinin-like protein (VSNL)-subfamily of NCS proteins, VILIP-1 and VILIP-3, reiterate some of the background information about these Ca2+-signaling proteins, and summarize the current knowledge about their effects on neuronal signaling, which may be of potential relevance for the understanding of their link to disease severity and early cognitive decline in AD
Summary
In the old scriptures it is said: neither do men put new wine into old bottles, else the bottles break, and the wine runneth out, and the bottles perish, but they put new wine into new bottles, and both are preserved (Matthew 9:17). In AD brains, an imbalance in the ratio of Ca2+-sensor (Calsenilin, VILIP-1) versus Ca2+-buffer proteins (CB/CR: calbindin-D28K, calretinin) in subpopulations of neurons may lead to their selective vulnerability and early loss, and, in turn, to the appearance of extracellular VSNLs, which are associated with the pathologic hallmarks amyloid plaques and neurofibrillary tangles (NFT).
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