Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment

David R Whitfield; Julie Vallortigara; Amani Alghamdi; David Howlett; Tibor Hortobágyi; Mary Johnson; Johannes Attems; Stephen Newhouse; Clive Ballard; Alan J Thomas; John T O'Brien; Dag Aarsland; Paul T Francis

doi:10.1016/j.neurobiolaging.2014.06.015

Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment

David R Whitfield, Julie Vallortigara, Amani Alghamdi, David Howlett, Tibor Hortobágyi, Mary Johnson, Johannes Attems, Stephen Newhouse, Clive Ballard, Alan J Thomas, John T O'Brien, Dag Aarsland, Paul T Francis

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Abstract

The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice and the protein has been associated with plaques. We investigated the levels of ZnT3 and PSD95, a marker of the post-synaptic terminal, in people with Parkinson’s disease dementia (PDD n=31), dementia with Lewy bodies (DLB n=44), Alzheimer’s disease (AD n=16) and controls (n=24), using semi-quantitative western blotting and immunohistochemistry in three cortical regions. Standardized cognitive assessments during life and semi-quantitative scoring of Aβ, tau and α-synuclein at post-mortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology.

Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p=0.001 and p=0.002 respectively), and between ZnT3 levels in the parietal cortex and cognitive impairment (p=0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of amyloid-β (p=0.003) and tau pathology (p=0.011). DLB and PDD were characterized by significant reductions of PSD95 (p<0.05) and ZnT3 (p<0.001) in prefrontal cortex compared to controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared to controls (p=0.02) and PDD (p=0.005).

This study has identified Zn2+ modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD, and the potential for synaptic proteins to be utilised as biomarkers for the differentiation of DLB and PDD from AD.

Original language	English
Pages (from-to)	2836-2844
Number of pages	9
Journal	Neurobiology of Aging
Volume	35
Issue number	12
DOIs	https://doi.org/10.1016/j.neurobiolaging.2014.06.015
Publication status	Published - Dec 2014

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Assessment of ZnT3 and PSD95_WHITFIELD_Accepted 10Jun2014_GREEN AAM
NOTICE: this is the author’s version of a work that was accepted for publication in Neurobiology of Aging. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication.
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Whitfield, D. R., Vallortigara, J., Alghamdi, A., Howlett, D., Hortobágyi, T., Johnson, M., Attems, J., Newhouse, S., Ballard, C., Thomas, A. J., O'Brien, J. T., Aarsland, D., & Francis, P. T. (2014). Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment. Neurobiology of Aging, 35(12), 2836-2844. https://doi.org/10.1016/j.neurobiolaging.2014.06.015

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title = "Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment",

abstract = "The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice and the protein has been associated with plaques. We investigated the levels of ZnT3 and PSD95, a marker of the post-synaptic terminal, in people with Parkinson{\textquoteright}s disease dementia (PDD n=31), dementia with Lewy bodies (DLB n=44), Alzheimer{\textquoteright}s disease (AD n=16) and controls (n=24), using semi-quantitative western blotting and immunohistochemistry in three cortical regions. Standardized cognitive assessments during life and semi-quantitative scoring of Aβ, tau and α-synuclein at post-mortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology.Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p=0.001 and p=0.002 respectively), and between ZnT3 levels in the parietal cortex and cognitive impairment (p=0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of amyloid-β (p=0.003) and tau pathology (p=0.011). DLB and PDD were characterized by significant reductions of PSD95 (p<0.05) and ZnT3 (p<0.001) in prefrontal cortex compared to controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared to controls (p=0.02) and PDD (p=0.005).This study has identified Zn2+ modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD, and the potential for synaptic proteins to be utilised as biomarkers for the differentiation of DLB and PDD from AD.",

author = "Whitfield, {David R} and Julie Vallortigara and Amani Alghamdi and David Howlett and Tibor Hortob{\'a}gyi and Mary Johnson and Johannes Attems and Stephen Newhouse and Clive Ballard and Thomas, {Alan J} and O'Brien, {John T} and Dag Aarsland and Francis, {Paul T}",

year = "2014",

month = dec,

doi = "10.1016/j.neurobiolaging.2014.06.015",

language = "English",

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journal = "Neurobiology of Aging",

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Whitfield, DR , Vallortigara, J , Alghamdi, A, Howlett, D, Hortobágyi, T, Johnson, M, Attems, J, Newhouse, S , Ballard, C, Thomas, AJ, O'Brien, JT, Aarsland, D & Francis, PT 2014, 'Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment', Neurobiology of Aging, vol. 35, no. 12, pp. 2836-2844. https://doi.org/10.1016/j.neurobiolaging.2014.06.015

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T1 - Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease

T2 - association with cognitive impairment

AU - Whitfield, David R

AU - Vallortigara, Julie

AU - Alghamdi, Amani

AU - Howlett, David

AU - Hortobágyi, Tibor

AU - Johnson, Mary

AU - Attems, Johannes

AU - Newhouse, Stephen

AU - Ballard, Clive

AU - Thomas, Alan J

AU - O'Brien, John T

AU - Aarsland, Dag

AU - Francis, Paul T

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N2 - The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice and the protein has been associated with plaques. We investigated the levels of ZnT3 and PSD95, a marker of the post-synaptic terminal, in people with Parkinson’s disease dementia (PDD n=31), dementia with Lewy bodies (DLB n=44), Alzheimer’s disease (AD n=16) and controls (n=24), using semi-quantitative western blotting and immunohistochemistry in three cortical regions. Standardized cognitive assessments during life and semi-quantitative scoring of Aβ, tau and α-synuclein at post-mortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology.Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p=0.001 and p=0.002 respectively), and between ZnT3 levels in the parietal cortex and cognitive impairment (p=0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of amyloid-β (p=0.003) and tau pathology (p=0.011). DLB and PDD were characterized by significant reductions of PSD95 (p<0.05) and ZnT3 (p<0.001) in prefrontal cortex compared to controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared to controls (p=0.02) and PDD (p=0.005).This study has identified Zn2+ modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD, and the potential for synaptic proteins to be utilised as biomarkers for the differentiation of DLB and PDD from AD.

AB - The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice and the protein has been associated with plaques. We investigated the levels of ZnT3 and PSD95, a marker of the post-synaptic terminal, in people with Parkinson’s disease dementia (PDD n=31), dementia with Lewy bodies (DLB n=44), Alzheimer’s disease (AD n=16) and controls (n=24), using semi-quantitative western blotting and immunohistochemistry in three cortical regions. Standardized cognitive assessments during life and semi-quantitative scoring of Aβ, tau and α-synuclein at post-mortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology.Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p=0.001 and p=0.002 respectively), and between ZnT3 levels in the parietal cortex and cognitive impairment (p=0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of amyloid-β (p=0.003) and tau pathology (p=0.011). DLB and PDD were characterized by significant reductions of PSD95 (p<0.05) and ZnT3 (p<0.001) in prefrontal cortex compared to controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared to controls (p=0.02) and PDD (p=0.005).This study has identified Zn2+ modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD, and the potential for synaptic proteins to be utilised as biomarkers for the differentiation of DLB and PDD from AD.

U2 - 10.1016/j.neurobiolaging.2014.06.015

DO - 10.1016/j.neurobiolaging.2014.06.015

M3 - Article

SN - 0197-4580

VL - 35

SP - 2836

EP - 2844

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 12

ER -

Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer's disease: association with cognitive impairment

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