A Molecular Analysis Of Prion Protein Expression In Alzheimer's Disease

In Prion Diseases, misfolding of neuronal prion protein (PrPC) to a pathogenic isomer (PrPSC) is associated with neuronal death. Previous pathological studies have demonstrated increased immunoreactivity of PrPC at Aβ plaques in Alzheimer's Disease, and it has been suggested that this either reflects a role for PrPC in the neuronal response to stress or is a feature of the neuropathogenesis of atypical subtypes of Alzheimer's disease. In this paper we utilised western blotting to examine the molecular characteristics of PrP in frozen Hippocampal tissue from 7 cases of Alzheimer's Disease in which prion protein expression was demonstrated by immunohistochemistry, before using Restriction Fragment Length Polymorphism (RFLP) methodology to define the genotype of the codon 129 polymorphism of PRNP in each case. We observed PrP accumulating as globular structures at A plaques, and within ependymal cells lining the lateral ventricle. Immunohistochemistry also showed that PrPC and Superoxide dismutase-1 where deposited in a similar pattern at Aβ plaques. Western blotting revealed that PrP in Alzheimer's disease is composed of the same 208-residue peptide expressed in non-diseased brain. Quantitative western blot analysis demonstrated increased levels of PrPC in a short duration case of Alzheimer's Disease, while, in the remaining cases, levels of PrPC decreased in parallel with increasing disease duration and decreasing brain mass. RFLP genotyping revealed that all codon 129 genotypes (M/M, M/V, V/V) were represented in our study cohort. Our data suggest that increased levels of PrPC may account for PrP immunoreactivity at plaques in Alzheimer's disease, and that PrP deposition is not restricted to certain atypical subtypes of Alzheimer's disease.

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Absence of association between codon 129/219 polymorphisms of the prion protein gene and Alzheimer's disease in Japan

Annals of Neurology ◽

10.1002/ana.10748 ◽

2003 ◽

Vol 54 (4) ◽

pp. 553-554 ◽

Cited By ~ 24

Author(s):

Takuya Ohkubo ◽

Yuji Sakasegawa ◽

Takashi Asada ◽

Toru Kinoshita ◽

Yuichi Goto ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prion Protein ◽

Protein Gene ◽

Prion Protein Gene ◽

Codon 129

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Prion protein expression in senile plaques in Alzheimer's disease

Acta Neuropathologica ◽

10.1007/s004010000271 ◽

2001 ◽

Vol 101 (1) ◽

pp. 49-56 ◽

Cited By ~ 65

Author(s):

I. Ferrer ◽

R. Blanco ◽

M. Carmona ◽

B. Puig ◽

R. Ribera ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Expression ◽

Prion Protein ◽

Senile Plaques

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Codon 129 polymorphism of prion protein gene in sporadic Alzheimer’s disease

European Journal of Neurology ◽

10.1111/j.1468-1331.2007.02021.x ◽

2008 ◽

Vol 15 (2) ◽

pp. 173-178 ◽

Cited By ~ 12

Author(s):

A. Poleggi ◽

A. Bizzarro ◽

A. Acciarri ◽

P. Antuono ◽

S. Bagnoli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prion Protein ◽

Protein Gene ◽

Prion Protein Gene ◽

Sporadic Alzheimer’S Disease ◽

Codon 129

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Differential expression of cellular Prion protein in neural development in Familial Alzheimer’s Disease

10.26226/morressier.5b31ec2b2afeeb001345a47e ◽

2018 ◽

Author(s):

Cleide Dos Santos Souza

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differential Expression ◽

Prion Protein ◽

Neural Development ◽

Cellular Prion Protein ◽

Familial Alzheimer’S Disease ◽

Familial Alzheimer's Disease

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Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

Cell Death and Differentiation ◽

10.1038/s41418-020-00685-9 ◽

2021 ◽

Author(s):

Wen-Dai Bao ◽

Pei Pang ◽

Xiao-Ting Zhou ◽

Fan Hu ◽

Wan Xiong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Impairment ◽

Iron Homeostasis ◽

Critical Role ◽

Gene Set Enrichment Analysis ◽

Molecular Characteristics ◽

Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

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Gene therapy-mediated enhancement of protective protein expression for the treatment of Alzheimer’s disease

Brain Research ◽

10.1016/j.brainres.2020.147264 ◽

2021 ◽

pp. 147264

Author(s):

Lauren V. Owens ◽

Alexandre Benedetto ◽

Neil Dawson ◽

Christopher J. Gaffney ◽

Edward T. Parkin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Therapy ◽

Protein Expression

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STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry

Journal of Molecular Medicine ◽

10.1007/s00109-018-1677-y ◽

2018 ◽

Vol 96 (10) ◽

pp. 1061-1079 ◽

Cited By ~ 22

Author(s):

Carlos Pascual-Caro ◽

Maria Berrocal ◽

Aida M. Lopez-Guerrero ◽

Alberto Alvarez-Barrientos ◽

Eulalia Pozo-Guisado ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Death ◽

Protein Expression ◽

Transmembrane Domain ◽

Neuroblastoma Cell ◽

Disease Patient ◽

List Type

Abstract STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. Key messages STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

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