Abstract
The neuronal Ca(2+)-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 Ca(2+)-homeostasis leading to neuronal loss. In PC12 cells, depending on co-expression with the neuroprotective Ca(2+)-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 Ca(2+)-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.