Supplemental material: Cognitive reserve, presynaptic proteins and dementia in the
elderly
William G. Honer, M.D., Alasdair M. Barr, Ph.D., Ken Sawada, M.D., Ph.D., Allen E.
Thornton, Ph.D., Martha Clare Morris, Sc.D., Sue E. Leurgans, Ph.D., Julie A. Schneider,
M.D., and David A. Bennett, M.D.
COGNITIVE RESERVE AND PRESYNAPTIC PROTEINS
2
Table S1. Presynaptic proteins studied in the present series. Research findings in Alzheimer’s disease reviewed
elsewhere.1
Protein
Antibody
Function
Localization
Neurological phenotype in
genetic mouse models
Clinical relevance (selected)
Synaptophysin
EP10
Unclear
Synaptic vesicle
membrane
Syp-/- mouse has subtle
defects in spatial learning and
memory14
Used as a marker for neural
and neuroendocrine tumors
Contributes to X-linked mental
retardation2
Syntaxin-1A/1B
SP6, SP7
One of three interacting
SNARE proteins
required for fusion of
synaptic vesicles to the
presynaptic membrane
Presynaptic
membrane
Stx1a-/- mouse has specific
memory consolidation
deficits13
Cleaved by botulinum
neurotoxin3
Deleted in Williams syndrome,
and expression level
contributes to cognitive
dysfunction12
SNAP-25
SP12
SNARE protein
Presynaptic
membrane
Snap25-/- mouse dies at
birth4
Cleaved by botulinum
neurotoxin3
Genetic polymorphisms
associated with variation in
cognitive function in healthy
persons and schizophrenia5, 6
VAMP-1/2
SP10
SNARE protein
Synaptic vesicle
membrane
Vamp2-/- mouse dies at
birth11
Cleaved by tetanus and
botulinum neurotoxins3
Complexin-I
SP33
Binds to and modifies
interactions between
proteins in the SNARE
complex
Presynaptic terminal
cytoplasm, enriched
in inhibitory terminals
Cplx1-/- mouse has severe
ataxia and social deficits10
Small postmortem study
shows association between
protein level and cognitive
dysfunction in schizophrenia7
Complexin-II
LP27
Binds to and modifies
interactions between
proteins in the SNARE
complex
Presynaptic terminal
cytoplasm, enriched
in excitatory
terminals
Cplx2-/- mouse has motor,
learning and memory deficits9
Genetic polymorphisms
associated with cognitive
dysfunction in schizophrenia8
COGNITIVE RESERVE AND PRESYNAPTIC PROTEINS
3
REFERENCES
1.
Honer WG. Pathology of presynaptic proteins in Alzheimer's disease: more than simple loss of terminals. Neurobiol
Aging 2003;24:1047-62.
2.
Tarpey PS, Smith R, Pleasance E, et al. A systematic, large-scale resequencing screen of X-chromosome coding
exons in mental retardation. Nat Genet 2009;41:535-43.
3.
Dolly JO, Lawrence GW, Meng J, Wang J, Ovsepian SV. Neuro-exocytosis: botulinum toxins as inhibitory probes
and versatile therapeutics. Curr Opin Pharmacol 2009;9:326-35.
4.
Washbourne P, Thompson PM, Carta M, et al. Genetic ablation of the t-SNARE SNAP-25 distinguishes
mechanisms of neuroexocytosis. Nat Neurosci 2002;5:19-26.
5.
Gosso MF, de Geus EJC, van Belzen MJ, et al. The SNAP-25 gene is associated with cognitive ability: evidence
from a family-based study in two independent Dutch cohorts. Molec Psychiatry 2006;11:878-86.
6.
Spellmann I, Müller N, Musil R, et al. Associations of SNAP-25 polymorphisms with cognitive dysfunctions in
Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. Eur Arch
Psychiatry Clin Neurosci 2008;258:335-44.
7.
Sawada K, Barr AM, Nakamura M, et al. Hippocampal complexin proteins and cognitive dysfunction in
schizophrenia. Arch Gen Psychiatry 2005;62:263-72.
COGNITIVE RESERVE AND PRESYNAPTIC PROTEINS
8.
4
Begemann M, Grube S, Papiol S, et al. Modification of cognitive performance in schizophrenia by complexin 2
gene polymorphisms. Arch Gen Psychiatry 2010;67:879-88.
9.
Glynn D, Bortnick RA, Morton AJ. Complexin II is essential for normal neurological function in mice. Hum Mol
Genet 2003;12:2431-48.
10.
Drew CJ, Kyd RJ, Morton AJ. Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to
be cognitively normal. Hum Mol Genet 2007;16:2288-305.
11.
Schoch S, Deak F, Konigstorfer A, et al. SNARE function analyzed in synaptobrevin/VAMP knock-out mice.
Science 2001;294:1117-22.
12.
Gao MC, Bellugi U, Dai L, et al. Intlligence in Williams syndrome is relatd to STX1A, which encodes a component
of the presynaptic SNARE complex. PLoS ONE 2010;5:e10292.
13.
Fujiwara T, Mishima T, Kofuji T, et al. Analysis of knock-out mice to determine the role of HPC-1/syntaxin 1A in
expressing synaptic plasticity. J Neurosci 2006;26:5767-76.
14.
Schmitt U, Tanimoto N, Seeliger M, Schaeffel F, Leube RE. Detection of behavioral alterations and learning deficits
in mice lacking synaptophysin. Neuroscience 2009;162:234-4
Table S2. Associations between presynaptic measures and global cognitive function (zscore).*
Terms
Model
Estimated
beta
coefficient
SE
P-value
Synaptophysin
0.08
0.08
0.31
Syntaxin
0.09
0.08
0.25
SNAP-25
0.05
0.08
0.55
VAMP
0.29
0.08
<0.001
Complexin-I
0.47
0.08
<0.001
Complexin-II
0.30
0.08
<0.001
Syntaxin-SNAP-25 interaction
0.27
0.08
0.001
* Models controlled for age, sex, education. Each presynaptic measure assessed separately.
Figure S1. Global cognitive function (z-score) illustrated for a female, age 88 with 14
years of education, representative of the sample. Percentiles of presynaptic proteins
VAMP, complexin-I, complexin-II and the SNAP-25-syntaxin interaction are shown as
colored lines (green: 90th percentile, limited by the amount of available data, red: 50th
percentile, blue: 10th percentile). Global cognitive function declines as AD pathology
increases, but may vary considerably depending on levels of presynaptic proteins and
protein-protein interactions.
Figure S2. Images of hippocampus (dentate granule cell layer) obtained with triple
immunostaining and confocal microscopy. Dark areas are unstained cell bodies,
punctate areas of immunostaining are presynaptic terminals. Upper left-to-right images
COGNITIVE RESERVE AND PRESYNAPTIC PROTEINS
6
show high overlap between SNAP-25, syntaxin and a marker for excitatory terminals,
the vesicular glutamate transporter-1 (vGlut). Lower left-to-right images show overlap of
SNAP-25 and syntaxin, but less overlap of these two presynaptic proteins with a marker
for inhibitory terminals, the vesicular GABA transporter (vGAT). Scale bar at upper left
represents 5 microns.