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 postsynaptic density protein 95 (PSD95), a marker of the postsynaptic 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 semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid β (Aβ), tau, and α-synuclein at postmortem 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 Aβ (p = 0.003) and tau (p = 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p = 0.02) and PDD (p = 0.005). This study has identified Zn(2+) modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD.
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Whitfield
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Vallortigara
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK; Biochemistry Department, College of Science, King Saud University, Riyahd, Saudi Arabia.
authors.forename: Amani
authors.initials: A
authors.lastname: Alghamdi
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Howlett
authors.affiliation: Department of Neuropathology, Institute of Pathology, University of Debrecen, Debrecen, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Johannes
authors.initials: J
authors.lastname: Attems
authors.affiliation: National Institute of Health Research Biomedical Research Centre for Mental Health, South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King's College London, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Newhouse
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
authors.forename: Clive
authors.initials: C
authors.lastname: Ballard
authors.affiliation: National Institute of Health Research Biomedical Research Centre for Mental Health, South London and Maudsley National Health Service Foundation Trust and Institute of Psychiatry, King's College London, London, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Thomas
authors.affiliation: Department of Psychiatry, University of Cambridge, Cambridge, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: Department of Neurobiology, Ward Sciences and Society, Karolinska Institute, Stockholm, Sweden; Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Aarsland
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London, UK. Electronic address: paul.francis@kcl.ac.uk.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D015415:Biomarkers / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D003071:Cognition; D003937:Diagnosis, Differential; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020961:Lewy Body Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D017397:Prefrontal Cortex / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D015415:Biomarkers; D027682:Cation Transport Proteins; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102806:SLC30A3 protein, human; D015032:Zinc
keywords: Alzheimer's disease; Amyloid β; Cognitive impairment; Dementia with Lewy bodies; Parkinson's disease with dementia; Synaptic dysfunction; Tau; Zinc