Transcriptional regulation of the Alzheimer

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• Transcriptional regulation of the Alzheimers
  disease gene, Presenilin-2

Ephrat Levy-Lahad, MD Shaare Zedek Medical Center
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Causative/deterministic AD genes

• APP (Amyloid Precursor protein)
• chromosome 21
• Presenilin 1 (PSEN1) chromosome 14
• Presenilin 2 (PSEN2) chromosome 1

Missense mutations Autosomal dominant inheritance
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Presenilin-1 mutations
http//www.molgen.ua.ac.be/ADMutations/default.cfm
?MT1ML1PageGraphicContextsPSEN1
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Presenilin-2 mutations
http//www.molgen.ua.ac.be/ADMutations/default.cfm
?MT1ML1PageGraphicContextsPSEN2
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APP Processing
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The ?-secretase complex
post
(? remnant)
PSEN- Presenilin (1 or 2) NCT- Nicastrin Aph-1
(anterior pharynx-defective 1) PEN2 (Presenilin
enhancer 2)
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PS mutation frequencies

• 
  PS1 PS2
• published pedigrees 50-70 rare
  
• population based
• FAD 18
  rare
• presenile AD (lt60 yr.) 6
  1
• Lleo et al, 2002, Arch Neurol 591759-63.
• Cruts et al. 1998, Hum Molec. Genet 743-51

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Clinico-pathological featuresPS2 vs. PS1
associated FAD

• PS2 PS1
• VG , Italian
• Age of onset (yr.) 54.9, gt60 30-55
• mean dis. duration (yr.)11.3 4.6 (20) 5.8-7.6
  (5-10)
• intrafamilial range (yr.) 40-75, 48-88
  30-78
• non-penetrance 89 yrs. 68,
  76 yrs.
• brain A? deposition sporadic AD at
  least X 2
• Mann et al, Ann Neurol 1996, 1997

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Transcriptional regulation of familial AD genes

• A?(42-43) ? - final common AD pathway (amyloid
  hypothesis)
• Amounts of APP/PS1/PS2 critical for A?(42-43)
  production.

Role for transcriptional regulation of
causative AD genes in AD pathology
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APP transcription and AD
Trisomy 21 APP overexpression (x4-5)
early, excess A?(42-43) APP
duplication causes dominant AD AD brains,
APP mRNA levels conflicting evidence
Cohen et al, PNAS, 1988 Rumble et al, New Engl
J Med, 1989 Rovelet-Lecrux,A. et al. Nat.
Genet. 38, 24-26 ,2006 Matsui,T et al Brain
Res. 1161, 116-123 (2007) Panegyres,PK et al J.
Neurol. Sci. 173, 81-92 (2000( Jacobsen JS et
al. Neurobiol. Aging 12, 585-592 (1991
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PS-2 transcription and AD

• Hippocampal PS-2 mRNA reduced in AD brains
  (75?)
• PS-2 overexpression pro-apoptotic.
• PS-2 expression modulated by various stimuli
  (cytokines, retinoic acid)

Takami et al, 1997 McMillan et al 2000
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PSEN2 expression
Levy-Lahad et al, 1996
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PSEN2 transcripts differ in 5UTR length
Renbaum et al, Gene. 2003318113-24.
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PSEN2 harbors two promoter regions
P1
P2
Renbaum et al, Gene. 2003318113-24.
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PSEN2 P1 promoter analysisMutagenesis of
putative transcription factor binding sites
Sp1 site - 83 of promoter activity
Renbaum et al, Gene. 2003318113-24.
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PSEN2 P2 promoter analysisMutagenesis of
putative Egr-1 binding sites
40 of activity
Renbaum et al, Gene. 2003318113-24.
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PS-2 P2 promoter analysisEffect of Egr-1
overexpression
Renbaum et al, Gene. 2003318113-24.
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Egr-1 binds the P2 promoter region
Renbaum et al, Gene. 2003318113-24.
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Transcriptional regulation of the Alzheimers
disease gene, Presenilin-2

• PS-2 is driven by dual promoter elements
• Upstream P1 housekeeping promoter
• Downstream P2 inducible by Egr-1, which binds
• to the P2
  seuquence.
• Egr-1 may modulate PS-2 protein levels, may be
  relevant to a role for PS-2 in synaptic
  plasticity.

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Egr-1 (early growth response)(aliases krox24,
zif268, NGFI-A, tis8)

• EGR transcription factor family
• Conserved DNA binding domain
• 3 Zinc finger motifs.
• Triggers immediate-early transcription in
  response to extra-cellular stimuli.
• Upregulates Thymidine kinase,
• PDGF, synapsins, AChE, NMDAR-1

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Egr-1 functions

• Synaptic plasticity Egr-1 induced by NGF,
  neurotransmittor-receptor stimulation
  depolarization.
• Memory paradigms/formation- Egr-1 induced by
• LTP, in songbirds by exposure to new songs/recall
  of tutored songs.
• Egr-1 activated in aversive learning in mice.
• Neuronal apoptosis- mediates A?-induced
  apoptosis, activates p73.

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Presenilins and synaptic plasticity

• PS1/PS2 conditional double KO (cortex)-
• age related, progressive neurodegeneration, AD
  neuropathology,including synaptic loss, neuronal
  cell death, astrogliosis and tau
  hyperphosphorylation
• PS1 conditional KO (forebrain) mice
• significant deficits in long-term spatial memory
  
• PS1 downregulation in p53 KO mice
• learning deficiency
• PS1 under-expressing mice (PS1 /-) deficient
  LTP

• The role of presenilins in learning/memory not
  simplistically related to ?-secretase activity on
  APP.

Saura et al , Neuron 2004. Yu et al, Neuron
2001 Amson et al, PNAS, 2000 Morton et
al Neurosci Lett 2002.
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Paul Renbaum, PhD Rachel Beeri, PhD MSc/PhD
students Merav Amiel Efrat Gabai Moran
Gal Hadile Ounallah Yael Zaltstein