Poster Presentations: P1 P363

index, and generalized brain atrophy. Neuropathologic endpointswere dichotomized to identify the most severely affected. Analyseswere by linear and logistic regression controlling for education andage at final testing, or for age at death.Results: The rs13381522SNPand ApoE ε4 were significantly and independently associated withdefinite cognitive impairment near the end of life, with comparablecoefficients. ApoE ε4 was significantly associated with all of theAD-related brain abnormalities (except generalized brain atrophy)with Odds Ratios of 2.0-5.6. The rs13381522 SNP was associatedwith higher Braak Stage (OR¼2.99; CI¼1.19-7.5) and neocorticalNP (OR¼2.64; CI¼1.0-6.9). Its association with neocortical NFTwas marginal (OR¼2.07; CI¼0.75-5.60). The rs3764479 SNPwas not associated with any endpoints, ApoE ε4, or rs13381522.Allele frequencies in this panel were 0.102 for ApoE ε4, 0.038 forrs13381522, and 0.211 for rs3764479. Conclusions: In autopsiedHAAS participants, TTR rs13381522 was associated with late lifecognitive impairment, Braak stage, and neocortical neuritic plaquecounts at strengths similar to those for ApoE ε4. Unlike ApoE ε4,this TTR SNP was not significantly associated with diffuse plaquecounts, hippocampal lesions, or CAA. The lower allele frequencyof rs13381522 may have contributed to these differences. Whileour findings implicate TTR rs13381522 SNP as a genetic risk factorfor the Alzheimer process, independent confirmation is essential.

P1-063 CORRELATION BETWEEN THE SYNAPTIC ZINC

TRANSPORTER ZNT3 AND ALPHA-SYNUCLEIN

IN DEMENTIA

Paul Francis1, David Whitfield2, Johannes Attems3, 1King’s College

London, London, United Kingdom; 2King’s College London, London,

United Kingdom; 3Newcastle University, Newcastle, United Kingdom.

Contact e-mail: paul.francis@kcl.ac.uk

Background: The loss of ZnT3 in mice has been implicated in age-related cognitive decline and pathological aggregation. Methods:

We investigated the importance of ZnT3 and a postsynaptic marker,PSD95, in people with Parkinson’s disease dementia (PDD n¼31),dementia with Lewy bodies (DLB n¼44), Alzheimer’s disease (ADn¼16) and controls (n¼24), using standardized cognitive assess-ments during life, semi-quantitative scoring of Abeta, tau andalpha-synuclein at post-mortem semi-quantitative western blottingand immunohistochemistry in three cortical regions. Concentra-tions of monomeric alpha synuclein were determined by commer-cially available ELISA. Furthermore, given the emergingrelationship between zinc and depression we examined the relation-ship of ZnT3 and scores for depression. Results: DLB and PDDwere characterized by significant reductions of PSD95 (p<0.05)and ZnT3 (p<0.001) in prefrontal cortex compared to controlsand AD. Strong associations were observed between ZnT3 andPSD95 levels in prefrontal cortex and cognitive impairment(p¼0.001 and p¼0.002 respectively). Associations were also seenbetween ZnT3 levels in cingulate cortex and severity of amyloid-beta (p¼0.003) and tau pathology (p¼0.011). Concentrations ofmonomeric alpha synuclein correlated positively with those ofZnT3 in all three regions (Rs 0.34-0.45, p<0.01). Reductions inZnT3 in BA9 were significantly associated with elevated depres-sion scores in the study cohort (beta¼-0.351(SE¼0.393)p¼0.0004). Conclusions: The relationship between ZnT3 andalpha-synuclein is Intriguing but as yet unexplained. However,this study has identified Zn2+ modulation as a novel target for thetreatment of cognitive impairment and depression in DLB and

PDD, and the potential for synaptic proteins to be utilised as bio-markers for the differentiation of DLB and PDD from AD.

P1-064 FIBRILS OFALPHA-SYNUCLEIN INTERACT

WITH PRION PROTEIN: A PUTATIVE OVERLAP

OF TWO NEURODEGENERATIVE DISEASES

Suzana Aulic, Elisa Isopi, Lara Masperone, Giuseppe Legname, SISSA,

Trieste, Italy. Contact e-mail: suzana.aulic@sissa.it

Background:Several reports imply cellular prion protein (PrPC) inbinding and modulating the toxicity of amyloids involved in neuro-degenerative disorders (such as Ab oligomers in Alzheimerdisease). In this work we investigated whether this is also true fora-synuclein (a-syn), a protein involved in neurodegeneration inParkinson disease (PD). Methods: Using the same methodologyadopted to obtain synthetic mammalian prions, we formed recom-binant mouse a-syn amyloids. Afterwards, we characterizedvarious preparations of a-syn amyloids (using atomic force micro-scopy and biochemical approaches) and subsequently explored theuptake of these preparations in neuroblastoma N2a cells which ex-press PrPC (N2aWT) and N2a cells knocked out for PrPC protein(N2aKO). Results: Our results show that the uptake of a-syn amy-loids is lower in N2aKO if compared to control cells. Confocal mi-croscopy and co-localization with sub-compartmental markersrevealed that the a-syn amyloids co-internalized with PrPC, accu-mulated and trafficked to lysosomes. Furthermore, serial passagesof N2aWT cells treated with a-syn amyloids led to sustained accu-mulation of both, a-syn and PrP. Further work was required to vali-date the importance of this interaction in disease progression invivo. Thus, we performed stereotaxic injections in substantia nigrapars compacta of a-syn amyloids in FVB PrPWT and FVB PrPKOmice.Conclusions: Our findings suggest a role for PrPC in regulatingof a-syn uptake, thus, evidencing a link between the two neurode-generation associated proteins. This study suggests an overlap be-tween prion disease and PD.

P1-065 ADAM10 AND BACE1 ARE LOCALIZED TO

SYNAPTIC VESICLES

Bengt Winblad1, Jolanta Lundgren2, Saheeb Ahmed3, Sophia Schedin-

Weiss2, Gunnar K. Gouras4, Lars O. Tjernberg2, Susanne Frykman2,1Karolinska Institutet, Stockholm, Sweden; 2Karolinska Institutet,

Huddinge, Sweden; 3European Neuroscience Institute, G€ottingen,

Germany; 4Lund University, Lund, Sweden.

Contact e-mail: bengt-winblad-swedishbrainpower@ki.se

Background: Despite the importance for the amyloid b-peptide(Ab) in Alzheimer Disease synaptic dysfunction, the subcellularproduction site and release mechanism for this peptide remainselusive. Elucidating these mechanisms would facilitate specific in-hibition of the production and/or secretion of Ab. Ab is producedby the sequential cleavage of Ab precursor protein (APP) by b-sec-retase (BACE1, forming the intermediate product APP C-terminalfragment b, APP-CTFb) and further by g-secretase. In an alterna-tive pathway, APP is instead cleaved by a-secretase (ADAM10)to form APP-CTFa, precluding Ab formation. We have previouslyshown that g-secretase is enriched in synaptic fractions but not inhighly pure synaptic vesicles. However, the synaptic localizationof ADAM10 and BACE1 remains to be determined.Methods:West-ern blot analysis and activity assays for ADAM10 and BACE1 wereperformed on highly pure synaptic vesicle fractions prepared from