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 languageEnglish
Pages (from-to)2836-2844
Number of pages9
JournalNeurobiology of Aging
Volume35
Issue number12
DOIs
Publication statusPublished - Dec 2014

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