GRIK4 blocking peptide

Introduction: We performed a comprehensive quantitative proteomics study on human hippocampus tissue involving all Braak stages to assess changes in protein abundance over the various stages of Alzheimer's disease (AD). Methods: Hippocampal subareas CA1 and subiculum of 40 cases were isolated using laser capture microdissection and analyzed using mass spectrometry. Immunoblotting and immunohistochemistry were used for validation. Results: Over the Braak stages, an altered expression was found for 372 proteins including changes in levels of extracellular matrix components, and in calcium-dependent signaling proteins. Early changes were observed in levels of proteins related to cytoskeletal dynamics and synaptic components including an increase in RIMS1 and GRIK4. Several synaptic proteins, such as BSN, LIN7A, DLG2, -3, and -4, exhibit an early-up, late-down expression pattern. Discussion: This study provides new insight into AD-dependent changes in protein levels in the hippocampus during AD pathology, identifying potential novel therapeutic targets and biomarkers. (C) 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Excitatory neurotransmitter dysfunction has been discussed to be involved in the pathophysiology of Alzheimer's disease (AD). In the current study we investigated gene and protein expression patterns of glutamatergic receptors and transporters in brains of AD patients in various stages of disease using gene chip arrays, real time PCR and immunohistochemistry. We found marked impairment in the expression of excitatory amino acid transporters (EAAT1 and EAAT2) at both gene and protein levels in hippocampus and gyrus frontalis medialis of AD patients, already in early clinical stages of disease. The loss of EAAT immunoreactivity was particularly obvious in the vicinity of amyloid plaques. In contrast, EAAT expression was up-regulated in the cerebellum of these patients. Furthermore, a significant up-regulation of the glutamatergic kainate (GRIK4) receptor observed by gene arrays was confirmed by quantitative RT-PCR in late stages in the hippocampus of AD patients. Moreover, there were down-regulations of other glutamatergic receptors such as NMDA (GRINL1A) and AMPA (GRIA4) receptors. Our data show marked changes in the functional elements of the glutamatergic synapses such as glutamatergic receptors and transporters and indicate impaired glutamate clearing rendering neurons susceptible to excess extracellular glutamate and support further the involvement of excitotoxic mechanisms in the pathogenesis of AD.