Synaptic changes in dementia: links to cognition and behaviour Paul T Francis, PhD Professor of Neurochemistry Director, Brains for Dementia Research
Agenda Discuss synaptic changes in various dementias Alzheimer s disease (AD) most common dementia 50-60% of all cases Vascular dementia - 20-25% Lewy body dementia (Dementia with Lewy bodies & Parkinson s disease dementia) 1520% (Frontotemporal dementia 10%)
Gross cerebral atrophy in AD
PET Imaging of Amyloid Deposits in Alzheimer s Disease vs Normal Controls PET imaging Pittsburgh Compound-B (PIB), can provide quantitative information on amyloid deposits in living subjects. Source: Klunk, et al. Ann Neurol 2004: 55:306-319.
Synaptic Pathology Alzheimer Normal Confocal images with anti-synaptophysin Robert Terry UCSD Reflected in FDG-PET
Synapse loss is crucial in the symptoms of dementia
Measuring synapses in human brain Major issues are they represent a small amount of total protein and that synapses may have cell bodies in different regions. Proteins synaptophysin is widely used as a general presynaptic marker; PSD95 as a postsynaptic marker. Specific markers of neurochemically defined synapses eg VGlut1 for cortical glutamate synapses. Postsynaptic markers include receptors such as NMDA.
Predicted energy use by grey matter Attwell and Iadecola TINS 25, 2002, Pages 621 625
VGlut1 in prefrontal cortex Kashani et al Neurobiol Aging 2007
Biphasic changes in VGlut1 in MCI and AD Bell, K. F. S. et al. J. Neurosci. 2007;27:10810-10817
Synaptophysin and VGluT 1 in AD R C AD AD C AD AD A B C kda 36.5 A 58 C D 58 D Mean relative intensity B E G F H 1 Control AD 0.8 0.6 0.4 0.2 * * * 0 Synaptophysin VGLUT1 VGLUT2 Kirvell et al, 2006 11
Glutamate glutamine cycle in AD Glutamatergic pyramidal neurone Reduced VGluT Glutamate Glutamine NMDA receptor Glutamate/glutamine transporter LOWER PEAK Signal impaired Glutaminase Ca2+ HIGHER BACKGROUND High noise Postsynaptic pyramidal neurone Damaged reuptake protein, reduced function Astroglial cell ATP
Lewy body dementias DLB -accounts for 15-20% of all dementia in old age but only widely recognised since mid-1990 s. PDD dementia in PD (48% cross-sectional, 78% cumulative). Cortical LBs stained for ubiquitin Lewy neurites stained for -synuclein
Patterns of atrophy in AD and DLB vs control AD DLB Bilateral: insula, and thalamus. Right side: inf parietal lobule, sup temporal gyrus, inf temporal gyrus. Left side: red nucleus and middle occipital gyrus Beyer, M. K. et al. Neurology 2007;69:747-754
Cases studied CONTROL DLB PDD AD Number of cases 24 50 33 16 Age of death 80.4 ± 1.4 81.7 ± 1.0 79.8 ± 1.1 88.0 ± 2.0 PMD (hours) 37.1 ± 6.4 42.9 ± 4.1 33.4 ± 2.9 25.4 ± 5.4 Gender M/F (%) 58 / 42 56 / 44 53 / 47 31/69 Brain ph 6.47 ± 0.07 6.52 ± 0.04 6.47 ± 0.06 6.30 ± 0.08 Detailed clinical information available for these cases: - Neuropathology report: Braak stage, CERAD, semi- quantitative scores of LBs, plaques and tangles - Cognitive and psychiatric tests: MMSE (mini-mental state examination) to assess cognitive decline Scoring of neuropsychiatric symptoms (frequency and intensity)
Mixed pathology in PDD/DLB PDD DLB Howlett et al, 2014
Correlates of cognitive decline in DLB/PDD n a-syn Ab NFT PSS BA9 65-68 0.390 0.071 0.234 0.353 BA21 65-69 0.477 0.0223 0.271 0.399 BA24 64-68 0.221 0.154 0.192 0.152 BA40 65-69 0.474 0.312 0.286 0.403 Values are for the Spearman correlation coefficient between average MMSE decline/year and semi-quantitative score for 3 types of pathology (0-3) and PSS a simple summation of those scores. Those highlighted in red are significant (p<0.05) Model 10 11 Standard Coeff Beta (Constant) NFT BA9 Ab BA21 a-syn BA21 (Constant) Ab BA21 a-syn BA21 -.151.280.491.206.479 t Sig..572-1.144 2.058 4.084.433 1.717 3.985.570.258.045.000.667.092.000 Howlett et al, 2014
Pathophysiological changes at synapses in DLB. A D, Brain homogenates of six confirmed DLB cases (D1 D6) are compared with age-matched non-dementia controls (C1 C6). Kramer M L, Schulz-Schaeffer W J J. Neurosci. 2007;27:1405-1410 2007 by Society for Neuroscience
Revealing previously undetectable, small granular α-synuclein aggregates with the PET blot. Kramer M L, Schulz-Schaeffer W J J. Neurosci. 2007;27:1405-1410
Role of SNARE proteins in vesicle docking TETHERING DOCKING PRIMING VAMP2 SNAP-25 MUNC-18 FUSION COMPLEXIN SYNTAXIN 1 Steps in vesicle fusion including tethering, docking, priming and fusion at the presynaptic membrane. These events are regulated by calcium and calcium binding proteins through their interaction with SNARE proteins, mechanism not shown here.
Pathways and systems regulating Zn2+ homeostasis in neurons Sensi, Bush et al 2009 Nature Rev Neurosci
The role of synaptic Zn2+ in the regulation of postsynaptic targets and synaptic plasticity Sensi, Bush et al 2009 Nature Rev Neurosci
Diagnosis (1 6) (3 4) 1.2 (1 4) 0.0 A D LB (1 3) (4 6) 1.2 D 0.4 D *** A 1.2 (4 0) D LB B D Diagnosis (3 1) 0.0 (3 4) *** PD D 0.4 PSD95 (relative units) 0.8 co nt ro l( 23 ) (1 6) (4 4) *** PD D 0.8 PSD95 (relative units) D LB A D (3 1) 1.2 co nt ro l( 17 ) D LB A D (3 3) C PD D co nt ro l( 24 ) A PD D co nt ro l( 21 ) Cingulate cortex ZnT3 (relative units) Frontal cortex ZnT3 (relative units) ZnT3 & PSD95 by diagnosis *** * * 0.8 0.4 0.0 Diagnosis * * 0.8 0.4 0.0 Diagnosis Whitfield et al, 2014 Neurobiol Aging in press
Relationship of ZnT3 to cognition and pathology ** *** * ZnT3 (relative units) 2.0 1.5 1.0 0.5 5 4 3 2 1 0 0.0 Classification of cognitive impairment Whitfield et al, 2014 Neurobiol Aging
Percentage of individuals according to depression score and diagnosis 100 90 80 PDD 70 DLB 60 AD 50 Control 40 30 20 10 0 absent mild Whitfield et al, 2014 AJGP in press moderate severe
ZnT3 concentration Zinc transporter 3 reduced in depression in dementia The ZnT3 concentration in frontal cortex is significantly different between depression groups 0 and 3. P=0.018 Severity of depression Whitfield et al, 2014 AJGP in press
Correlations with clinical features: depression Munc 18 BA9 2 1.5 * Munc 18 BA24 ** * 2 * 1.5 ** 1 1 0.5 0.5 absent 0 0 intermittent mild N= 27 for absent N= 22 for intermittent mild N= 12 for intermittent significant N= 11 for persistent intermittent significant persistant N= 28 for absent N= 23 for intermittent mild N= 12 for intermittent significant N= 11 for persistent Level of Munc18 protein expression decreased with the severity of Depression Julie Vallortigara
α-synuclein by ELISA in Frontal cortex ### ### ** *** *** a-synuclein expression / LB pathology BA9 One-way ANOVA F(3,100)=67.85, p<0.001; Bonferroni post-hoc test One-way ANOVA F(3,96)=10.46, p<0.001; Bonferroni post-hoc test
Correlations between α-synuclein (ELISA) and ZnT3 concentrations in DLB &PDD Rs =0.341, p=0.008, n=59 Rs =0.451, p=0.001, n=51 Rs =0.418, p=0.001, n=64 No correlations with α-synuclein pathology scores in any region David Whitfield & Julie Vallortigara (unpublished data)
A model for inhibition of exocytosis by large α-syn oligomers Adapted from Choi et al., PNAS 2013.
Summary and conclusions Synaptic changes occur all various dementias Changes are different for each dementia and often different cerebral regions are affected. Synaptic changes may represent an early change and therefore provide an opportunity for early identification and novel treatment targets.
Acknowledgements London Clive Ballard, Tibor Hortobagyi, David Whitfield, Julie Vallortigara, David Howlett, Amani Alghamdi. Newcastle - Johannes Attems, Alan Thomas, John O Brien. Stavanger/Stockholm - Dag Aarsland, Jean-Ha Baek, Erika Bereczki, Mohammed Seed Ahmed.
Synaptic changes in dementia: links to cognition and behaviour Paul T Francis, PhD Professor of Neurochemistry Director, Brains for Dementia Research