1
change, especially in rural locations, is a key issue because if all staff are not in someway involved, then sustained and enduring change is unlikely. How- ever, educational research shows us that human beings need regular, fre- quent repetition of information in order to learn it, adopt and sustain change. Post training support is essential to facilitate the sustained adoption of new workplace care actions. This paper reports on a unique educational component of a project funded by the Australian Government Department of Health and Ageing under the Encouraging Best Practice in Residential Aged Care program. The aim of the overall project is to develop implemen- tation strategies to address behaviours of concern by creating dementia friendly environments in seven rural residential aged care facilities in Vic- toria, Australia. This presentation focuses on the development and imple- mentation of ‘micro-training’ to support the translation of knowledge into practice as part of routine work schedules. Micro-training has been specif- ically developed to address issues of sustainability following education. Methods: The purpose of the micro-training is to provide daily contact with the core ideas of best practice in person-centred dementia care. De- signed to be used in small group opportunities such as shift change/hand- overs, micro-training is a one minute piece of video followed by a question for the group to answer in discussion for about another minute or two. The e-resource comprises 20 one minute video presentations, each one a message linked to principles of person-centred dementia care to ad- dress behaviours of concern. Results: Results indicate that even poorly re- sourced rural residential care facilities can benefit from micro-training in supporting the introduction of evidence-based practice. Conclusions: The micro-training approach is a simple approach to promoting shared values to implement and sustain best practice. The value of linking messages to key quality and accreditation documents is important. P4-030 ELEVATED AMYLOID-BETA IMPAIRS PROTEIN SUMOYLATION Linda Lee, Elena Dale, Agnes Staniszewski, Hong Zhang, Francesco Michelassi, Mikako Sakurai, Chintan Kapadia, Ottavio Arancio, Columbia University, New York, NY, USA. Contact e-mail: ll2429@ columbia.edu. Background: SUMOylation is a highly conserved post-translational mod- ification in which a 11 kDa protein, SUMO (small ubiquitin-like modifier), is covalently attached to target substrates. This modification can affect many aspects of protein function and localization and has been recently found to have multiple roles in neuronal physiology. Our lab has demon- strated that SUMOylation is a novel modulator of normal synaptic plastic- ity and memory in the hippocampus. When SUMOylation is acutely inhibited, both ex-vivo long-term potentiation (LTP) and hippocampal- dependent memory tasks are significantly impaired. Since synaptic and cognitive deficits are prominent characteristics of Alzheimer’s Disease, we have also investigated how SUMOylation may be involved in amy- loid-beta (Ab) induced pathology. Methods: Using ex-vivo hippocampal slice electrophysiology, we tested CA3-CA1 LTP with exposure to oligo- meric Ab42 (200nM) while manipulating SUMOylation levels with re- combinant transduction proteins; these constructs feature the HIV-1 TAT domain linked to either wild-type or a dominant negative version of Ubc9, the sole E2 SUMO ligase. Results: We initially observed that hippo- campal slices from aged APP and APP/PS1 transgenic mice do not exhibit increases in overall SUMOylation levels following LTP induction by theta- burst stimulation, as is observed in control wild type slices. Following this observation, we demonstrated next that LTP is significantly impaired to a similar degree with either Ab42 exposure or SUMOylation knockdown by the dominant negative Ubc9 (TAT-Ubc9dn). However, the Ab-mediated impairment is completely rescued with concurrent application of the wild- type Ubc9 construct (TAT-Ubc9wt). In a similar manner, hippocampal-de- pendent memory tasks are also impaired by either Ab42 or TAT-Ubc9dn injected into the dorsal hippocampi via cannulas. Performance in both the Morris water maze and contextual fear conditioning is significantly worsened with either treatment. As with the LTP experiments, enhancing SUMOylation with TAT-Ubc9wt proteins completely rescues these Ab- induced learning deficits. Conclusions: Our data strongly suggest that SUMOylation is impaired under pathological elevated Ab conditions and could be a mediating factor in the synaptic and cognitive deficits of Alz- heimer’s Disease. P4-031 SORCS1 ALTERS APP PROCESSING AND VARIANTS MAY INCREASE ALZHEIMER’S DISEASE RISK Christiane Reitz 1 , Shinya Tokuhiro 2 , Lorraine Clark 1 , Christopher Conrad 1 , Jean-Paul Vonsattel 1 , Raphael Lantigua 1 , Martin Medrano 3 , Irene Simkin 4 , Jonathan Haines 5 , Margaret Pericak- Vance 6 , Lindsay Farrer 7 , Joseph Lee 1 , Ekaterina Rogaeva 2 , Peter St.George- Hyslop 2 , Richard Mayeux 1 , 1 Columbia University, New York, NY, USA; 2 University of Toronto, Toronto, ON, Canada; 3 Universidad Tecnolo´gica de Santiago, Santiago, Dominican Republic; 4 Boston University School of Medicine, Boston, MA, USA; 5 Vanderbilt University Medical Center, Nas- ville, TN, USA; 6 University of Miami, Miami, FL, USA; 7 Boston University Schools of Medicine, Boston, MA, USA. Contact e-mail: cr2101@columbia. edu. Background: Sorting mechanisms that cause the amyloid precursor pro- tein (APP) and the b- and g-secretases to colocalize in the same compart- ment play an important role in the regulation of Ab production in Alzheimer’s disease (AD). We and several groups have reported that ge- netic variants in the Sortilin-related receptor (SORL1) increased the risk of AD, that SORL1 is involved in trafficking of APP, and that under-ex- pression of SORL1 leads to over-production of Ab. We now explored the role of one of its homologues, the sortilin-related VPS10 domain contain- ing receptor 1 (SORCS1), in AD. Methods: We analyzed the genetic asso- ciations between AD and 16 SORCS1-SNPs in six independent data sets (2809 cases and 3482 controls). In addition, we compared SORCS1 expres- sion levels of affected and unaffected brain regions in AD and control brains in microarray gene expression and RT-PCR sets, explored the effects of significant SORCS1-SNPs on SORCS1 brain expression levels, and ex- plored the effect of suppression and over expression of the common SORCS1 isoforms on APP processing and Ab generation. Results: In- herited variants in SORCS1 were associated with AD in all datasets (0.001 < p < 0.049). In addition, SorCS1 influenced APP processing. While over expression of SorCS1 reduced g-secretase activity and Ab levels, the suppression of SorCS1 increased g-secretase processing of APP and the levels of Ab. Conclusions: These data suggest that inherited or acquired changes in SORCS1 expression or function may play a role in the pathogenesis of AD. P4-032 QUANTITATIVE AND QUALITATIVE ANALYSIS OF INTRUSIONS, FALSE POSITIVES AND PERSEVERATIONS IN A MEMORY TEST IN PATIENTS WITH MEMORY COMPLAINTS Magdalena M. Caceres, Ignacio Acun ˜a, Jose N. Bernhardt, Paola Premolo, Federico Scabuzzo, Sofia Tillard, Sanatorio Allende, Cordoba, Argentina. Contact e-mail: [email protected]. Background: For the early diagnosis of Alzheimer’s disease (AD) is im- portant to investigate potential preclinical indicators.Several studies indi- cates the importance of characterize the errors types as well as the time in which they appear and their specificity .Thus the cuali and cuantitative analysis of the type of errors produced in a memory test could be useful to identify risk population and may be used as potential screening cognitive markers adding support to a early clinical diagnosis Methods: Thus the present study analizes the perseverations (P), types of intrusions (I) and rec- ognition false positive (FPr) in a test of verbal episodic memory (TAVEC spanish) in patients who consulted for mnemonic failures. The sample was divided into three subgroups: 17 patients with Mild Cognitive Impair- ment subtype Amnestic (MCIa) and 50 patients without MCI, subdivided into 27 controls without depression (C) and 23 controls with depression (CD). Data were analyzed using descriptive statistics and nonparametric ANOVA. Results: The results indicated that the number of false positives discriminate MCIa group of controls, being the FP unrelated (0.015) and the stimuls nonrelated of the B list (0.002) a strong indicator. Besides, there Hot Topics e29

Elevated Amyloid-beta Impairs Protein Sumoylation

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Hot Topics e29

change, especially in rural locations, is a key issue because if all staff are not

in someway involved, then sustained and enduring change is unlikely. How-

ever, educational research shows us that human beings need regular, fre-

quent repetition of information in order to learn it, adopt and sustain

change. Post training support is essential to facilitate the sustained adoption

of new workplace care actions. This paper reports on a unique educational

component of a project funded by the Australian Government Department

of Health and Ageing under the Encouraging Best Practice in Residential

Aged Care program. The aim of the overall project is to develop implemen-

tation strategies to address behaviours of concern by creating dementia

friendly environments in seven rural residential aged care facilities in Vic-

toria, Australia. This presentation focuses on the development and imple-

mentation of ‘micro-training’ to support the translation of knowledge into

practice as part of routine work schedules. Micro-training has been specif-

ically developed to address issues of sustainability following education.

Methods: The purpose of the micro-training is to provide daily contact

with the core ideas of best practice in person-centred dementia care. De-

signed to be used in small group opportunities such as shift change/hand-

overs, micro-training is a one minute piece of video followed by

a question for the group to answer in discussion for about another minute

or two. The e-resource comprises 20 one minute video presentations, each

one a message linked to principles of person-centred dementia care to ad-

dress behaviours of concern. Results: Results indicate that even poorly re-

sourced rural residential care facilities can benefit from micro-training in

supporting the introduction of evidence-based practice. Conclusions: The

micro-training approach is a simple approach to promoting shared values

to implement and sustain best practice. The value of linking messages to

key quality and accreditation documents is important.

P4-030 ELEVATED AMYLOID-BETA IMPAIRS PROTEIN

SUMOYLATION

Linda Lee, Elena Dale, Agnes Staniszewski, Hong Zhang,

Francesco Michelassi, Mikako Sakurai, Chintan Kapadia, Ottavio Arancio,

Columbia University, New York, NY, USA. Contact e-mail: ll2429@

columbia.edu.

Background: SUMOylation is a highly conserved post-translational mod-

ification in which a 11 kDa protein, SUMO (small ubiquitin-like modifier),

is covalently attached to target substrates. This modification can affect

many aspects of protein function and localization and has been recently

found to have multiple roles in neuronal physiology. Our lab has demon-

strated that SUMOylation is a novel modulator of normal synaptic plastic-

ity and memory in the hippocampus. When SUMOylation is acutely

inhibited, both ex-vivo long-term potentiation (LTP) and hippocampal-

dependent memory tasks are significantly impaired. Since synaptic and

cognitive deficits are prominent characteristics of Alzheimer’s Disease,

we have also investigated how SUMOylation may be involved in amy-

loid-beta (Ab) induced pathology. Methods: Using ex-vivo hippocampal

slice electrophysiology, we tested CA3-CA1 LTP with exposure to oligo-

meric Ab42 (200nM) while manipulating SUMOylation levels with re-

combinant transduction proteins; these constructs feature the HIV-1 TAT

domain linked to either wild-type or a dominant negative version of

Ubc9, the sole E2 SUMO ligase. Results:We initially observed that hippo-

campal slices from aged APP and APP/PS1 transgenic mice do not exhibit

increases in overall SUMOylation levels following LTP induction by theta-

burst stimulation, as is observed in control wild type slices. Following this

observation, we demonstrated next that LTP is significantly impaired to

a similar degree with either Ab42 exposure or SUMOylation knockdown

by the dominant negative Ubc9 (TAT-Ubc9dn). However, the Ab-mediated

impairment is completely rescued with concurrent application of the wild-

type Ubc9 construct (TAT-Ubc9wt). In a similar manner, hippocampal-de-

pendent memory tasks are also impaired by either Ab42 or TAT-Ubc9dn

injected into the dorsal hippocampi via cannulas. Performance in both

the Morris water maze and contextual fear conditioning is significantly

worsened with either treatment. As with the LTP experiments, enhancing

SUMOylation with TAT-Ubc9wt proteins completely rescues these Ab-

induced learning deficits. Conclusions: Our data strongly suggest that

SUMOylation is impaired under pathological elevated Ab conditions and

could be a mediating factor in the synaptic and cognitive deficits of Alz-

heimer’s Disease.

P4-031 SORCS1 ALTERS APP PROCESSING AND

VARIANTS MAY INCREASE ALZHEIMER’S

DISEASE RISK

Christiane Reitz1, Shinya Tokuhiro2, Lorraine Clark1,

Christopher Conrad1, Jean-Paul Vonsattel1, Raphael Lantigua1,

Martin Medrano3, Irene Simkin4, Jonathan Haines5, Margaret Pericak-

Vance6, Lindsay Farrer7, Joseph Lee1, Ekaterina Rogaeva2, Peter St.George-

Hyslop2, Richard Mayeux1, 1Columbia University, New York, NY, USA;2University of Toronto, Toronto, ON, Canada; 3Universidad Tecnologica de

Santiago, Santiago, Dominican Republic; 4Boston University School of

Medicine, Boston, MA, USA; 5Vanderbilt University Medical Center, Nas-

ville, TN, USA; 6University of Miami, Miami, FL, USA; 7Boston University

Schools of Medicine, Boston, MA, USA. Contact e-mail: cr2101@columbia.

edu.

Background: Sorting mechanisms that cause the amyloid precursor pro-

tein (APP) and the b- and g-secretases to colocalize in the same compart-

ment play an important role in the regulation of Ab production in

Alzheimer’s disease (AD). We and several groups have reported that ge-

netic variants in the Sortilin-related receptor (SORL1) increased the risk

of AD, that SORL1 is involved in trafficking of APP, and that under-ex-

pression of SORL1 leads to over-production of Ab. We now explored the

role of one of its homologues, the sortilin-related VPS10 domain contain-

ing receptor 1 (SORCS1), in AD. Methods: We analyzed the genetic asso-

ciations between AD and 16 SORCS1-SNPs in six independent data sets

(2809 cases and 3482 controls). In addition, we compared SORCS1 expres-

sion levels of affected and unaffected brain regions in AD and control

brains in microarray gene expression and RT-PCR sets, explored the effects

of significant SORCS1-SNPs on SORCS1 brain expression levels, and ex-

plored the effect of suppression and over expression of the common

SORCS1 isoforms on APP processing and Ab generation. Results: In-

herited variants in SORCS1 were associated with AD in all datasets

(0.001 < p < 0.049). In addition, SorCS1 influenced APP processing.

While over expression of SorCS1 reduced g-secretase activity and Ab

levels, the suppression of SorCS1 increased g-secretase processing of

APP and the levels of Ab. Conclusions: These data suggest that inherited

or acquired changes in SORCS1 expression or function may play a role in

the pathogenesis of AD.

P4-032 QUANTITATIVE AND QUALITATIVE ANALYSIS OF

INTRUSIONS, FALSE POSITIVES AND

PERSEVERATIONS IN A MEMORY TEST IN

PATIENTS WITH MEMORY COMPLAINTS

Magdalena M. Caceres, Ignacio Acuna, Jose N. Bernhardt,

Paola Premolo, Federico Scabuzzo, Sofia Tillard, Sanatorio Allende,

Cordoba, Argentina. Contact e-mail: [email protected].

Background: For the early diagnosis of Alzheimer’s disease (AD) is im-

portant to investigate potential preclinical indicators.Several studies indi-

cates the importance of characterize the errors types as well as the time

in which they appear and their specificity .Thus the cuali and cuantitative

analysis of the type of errors produced in a memory test could be useful

to identify risk population and may be used as potential screening cognitive

markers adding support to a early clinical diagnosis Methods: Thus the

present study analizes the perseverations (P), types of intrusions (I) and rec-

ognition false positive (FPr) in a test of verbal episodic memory (TAVEC

spanish) in patients who consulted for mnemonic failures. The sample

was divided into three subgroups: 17 patients with Mild Cognitive Impair-

ment subtype Amnestic (MCIa) and 50 patients without MCI, subdivided

into 27 controls without depression (C) and 23 controls with depression

(CD). Data were analyzed using descriptive statistics and nonparametric

ANOVA. Results: The results indicated that the number of false positives

discriminate MCIa group of controls, being the FP unrelated (0.015) and

the stimuls nonrelated of the B list (0.002) a strong indicator. Besides, there