neuroscience 2004 teaching in neuroscience session # 30.7 cholesterol homeostasis failure: a...
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Neuroscience 2004 Teaching in Neuroscience session # 30.7
CHOLESTEROL CHOLESTEROL HOMEOSTASIS FAILURE: HOMEOSTASIS FAILURE:
A UNIFYING CAUSE OF A UNIFYING CAUSE OF
SYNAPTIC DEGENERATION ?SYNAPTIC DEGENERATION ?Natalia V. Koudinova, Temirbolat T. Berezov Natalia V. Koudinova, Temirbolat T. Berezov
& Alexei R. Koudinov& Alexei R. Koudinov
Russia, IsraelAlso, please see slide show notes article next to this poster board
ISSN 1683-5506 / Copyright © 2004 by NV Koudinova et al. licensee Neurobiology of LipidsTo cite this article, use: Neurobiol. Lipids 3, 7 (2004), available at: http://neurobiologyoflipids.org/content/3/7/
This document is Acrobat .PDF imprint of the teaching poster slide show presented at the 34 th SFN Annual Meeting, 23-27 October 2004, San Diego, CA. To read web enhanced proceedings article and provide comments, go to: http://neurobiologyoflipids.org/content/3/7/
Cholesterol and synaptic plasticity:
Experimental system 1:Experimental system 1:
Naive albino vistar rats, acute cholesterol modulation in the hippocampal slices ex
vivoExperimental system 2:Experimental system 2:
albino vistar rats fed 2% cholesterol diet
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Experimental design
Incubation Incubation with cholesterol with cholesterol
acceptorsacceptors
Metabolic labeling Metabolic labeling withwith 3 3H-cholesterol H-cholesterol
or or 1414C-cholineC-choline
Electro-physiology
Immunofluorescent analysis
Efflux analysisFST catalog
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Biochemical Analysis of cholesterol and phospholipid Biochemical Analysis of cholesterol and phospholipid efflux from rat hippocampal slices after incubation with efflux from rat hippocampal slices after incubation with
cyclodextrin and CSF-HDLcyclodextrin and CSF-HDL
FASEB J 2001( Science 2002 )
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Cyclodextrine (cholesterol acceptor)
Fluorescent analysis of increased cholesterol efflux from rat hippocampal slices by staining with filipin
6h MCD, CA1 SR, higher x
Note cholesterol depleted SR neuronal processes (middle panel and to the
right) and pyramidal (top) and granule (bottom) cell layers in this
column of images.Navigate to our FASEBJ2001 article
at our Internet Office for better image quality and further discussion
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
control
cyclodextrine
B/C.B/C. Synaptic Synaptic Plasticity (LTP)Plasticity (LTP)
D. D. Presynaptic Presynaptic Mechanisms (PPF)Mechanisms (PPF)
A.A. Basic synaptic Basic synaptic function function ((I/O)I/O)
Cholesterol Cholesterol dynamicsdynamicsaffects:affects:
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Cholesterol and synaptic plasticityCholesterol and synaptic plasticity
I/OI/O
PPFPPF
control
cyclodextrine
cyclodextrine
control
LTPLTP
FASEB J 2001( Science 2002 )
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
control cyclodextrine
control
cyclodextrine
Paired PulsePaired PulseFacilitationFacilitation study study ((PPF)PPF)
NIH Alzheimer’s booklet
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Increased Increased cholesterol cholesterol
Dynamics causes Dynamics causes NFT(PHF)-like NFT(PHF)-like
excessive excessive phosphorylation phosphorylation of TAU in the of TAU in the hippocampus. hippocampus.
-- see framed -- see framed panel E – it shows panel E – it shows CA3 staining with CA3 staining with monoclonal AT8 monoclonal AT8
antibody, antibody, detecting PHF-taudetecting PHF-tau
No MCD, Z1
No MCD, TAU1
MCD, AT8
MCD, TAU1
No MCD, Z1
MCD, Z1 FASEB J 2001( Science 2002 )
12
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Normal Neuron
Microtubules
Neurofibrillary tangles
Degenerativeneuron
Neurofibrillary tangles (NFT)Neurofibrillary tangles (NFT)
NIH Alzheimer’s booklet
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Cholesterol-dependent change in neurofilament integrityCholesterol-dependent change in neurofilament integrityN
o M
No
M C
DC
DMM
CD
CD
FASEB J 2001CA1 Stratum Radiatum (SR) CA1SR, higher x DG, Insets: DG, higher x
FASEB J 2001
CONTROL
MCD
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
A staining shows no effect
of acute cholesterol
modulation on A staining
pattern_________
Slide to follow: chronic cholesterol modulation
affects A
INT
AC
T C
HO
LIN
TA
CT
CH
OL
AC
UT
E
CH
OL
A
CU
TE
C
HO
L
EF
FL
UX
, ME
FF
LU
X, M
CD
CD
FASEB J 2001
CA1SUBKoudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiol Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Chronic brain cholesterol homeostasis disbalance may cause Alzheimer’s like amyloid neurobiochemistry change (B-E) and
synaptic plasticity failure (F)
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
AA is an HDL protein constituent is an HDL protein constituent
LipoproteinLipoproteinparticleparticle
Amyloid beta
Soluble A is an apolipoprotein constituent of plasma and CSF HDL (HDL3) and CNS lipoproteins
(Koudinov et al. BBRC ‘1994, 1996, CCA’98, FASEB J ’98, many reports by others)
Chem and Life (in Russian): Jan 1998
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
AA in in Alzheimer’s Alzheimer’s CSF HDL CSF HDL
has has different different
distribution distribution comparedcomparedto normal to normal
CSFCSF6E10 Fluorogram Neurosci Lett 2001
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Function of amyloid beta in lipid Function of amyloid beta in lipid metabolism (1996-2001)metabolism (1996-2001)
Neurochem Res ‘2000, FASEB J ‘2001
• Inhibition of cholesterol esterificationInhibition of cholesterol esterification• Inhibition of cholesterol and phospholipid synthesis in Inhibition of cholesterol and phospholipid synthesis in
liver cellsliver cells
• Increase of cholesterol and phospholipid synthesis by Increase of cholesterol and phospholipid synthesis by amyloid beta in PC12, primary neuronal cells, in fetal amyloid beta in PC12, primary neuronal cells, in fetal
rat brain, and in adult rat slicesrat brain, and in adult rat slices• Inhibition of cholesterol and phospholipid synthesis in Inhibition of cholesterol and phospholipid synthesis in
fetal rat liverfetal rat liver
Koudinov et al. BMBI ‘1996, FEBS Lett ‘1997, FASEB J ‘1998
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Fluorescence microscopy
of labeled amyloid in neuronal cell culture: the mechanism of A
action on lipid synthesis remain
obscure.
Neurochem Res ‘2000
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Amyloid beta, LTP and hippocampal Amyloid beta, LTP and hippocampal lipid synthesislipid synthesis
FASEB J 2001( Science 2002 )
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
CONDITIONS HAVING CHANGED CONDITIONS HAVING CHANGED AMYLOID AMYLOID and/or TAU NEUROCHEMISTRY and/or TAU NEUROCHEMISTRY
NIH Alzheimer’s booklet
Alzheimer’s disease (AAlzheimer’s disease (A/TAU)/TAU)
Cardiovascular disease (ACardiovascular disease (A))Down syndrome (ADown syndrome (A))
Frontotemporal dementia (TAU) Frontotemporal dementia (TAU) Inclusion-body myositis (AInclusion-body myositis (A, TAU), TAU)ALS (TAU, AALS (TAU, A in brain/skin) in brain/skin)Parkinson disease (TAU)Parkinson disease (TAU)________________________________________________________
Normal early postnatal development Normal early postnatal development (TAU, not known for A(TAU, not known for A))Normal aging (ANormal aging (A))
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
What about different neurodegenerative diseases ?
* ** *
Is there a relevance
of this part of the cascade to other
neurodegenerative diseases ?
---------
If so, is there a neurodegeneration
specificity?
In Parkinson disease, for example, synaptic function
break may be due to a primary break of the
forebrain dopamine system
This scheme was first developed by us to explain the pathogenesis of Alzheimer’s
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Free open access at:
http://neurobiologyoflipids.org
Cholesterol and Alzheimer’sKoudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Cholesterol and Down syndromeCholesterol and Down syndrome
CCholesterol esterification abnormalityholesterol esterification abnormality in DS in DS patientspatients
SSpecific pathway of the liver sterol regulatory pecific pathway of the liver sterol regulatory element binding protein (SREBP) activation with element binding protein (SREBP) activation with
sterol-independent maturation of SREBP-1sterol-independent maturation of SREBP-1
HHigh circulating and tissue cholesterol levels in the igh circulating and tissue cholesterol levels in the fetusesfetuses
Lacko AG et al.. Clin Chim Acta. 132, 133 (1983).Diomede L, et al. BBRC. 260, 503 (1999).
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
NMJ and ANMJ and AAPP metabolismAPP metabolism
Askanas V, et al. Neurosci Lett 1992 143: 96-100.
1992 - the first demonstration of the amyloid precursor 1992 - the first demonstration of the amyloid precursor protein (APP) and Aprotein (APP) and A sequences concentrated sequences concentrated
postsynaptically at human neuro-muscular junctions postsynaptically at human neuro-muscular junctions (NMJs). (NMJs).
Conclusion: APP may have a role in normal junction biology Conclusion: APP may have a role in normal junction biology and possibly in some diseases affecting NMJs.and possibly in some diseases affecting NMJs.
Torroja L, et al. J Neurosci 1999 19: 7793-803.
1999 - The Drosophila APP homolog promotes 1999 - The Drosophila APP homolog promotes synapse differentiation at the neuromuscular synapse differentiation at the neuromuscular
junction.junction.
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
A restores hippocampal
LTP,
cholesterol synthesis inhibition
absorbs the restorative
action of the peptide
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Cholesterol and Inclusion-body Cholesterol and Inclusion-body myositis (IBM)myositis (IBM)
IBM vacuolated muscle fibers (VMF) IBM vacuolated muscle fibers (VMF) had strong LDLR- and VLDLR-immunoreactive had strong LDLR- and VLDLR-immunoreactive inclusions, which colocalized with Abeta, APOE, inclusions, which colocalized with Abeta, APOE,
p-tau, and free cholesterol. p-tau, and free cholesterol.
CONCLUSIONS:CONCLUSIONS:
Abnormal accumulation of LDLR, VLDLR, LRP, and Abnormal accumulation of LDLR, VLDLR, LRP, and cholesterol within IBM vacuolated muscle fibers cholesterol within IBM vacuolated muscle fibers suggests novel roles for them in the pathogenesis suggests novel roles for them in the pathogenesis
of the inclusion-body myositis.of the inclusion-body myositis.
Jaworska-Wilczynska et al. Neurology 2002; 58: 438.
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Apo E and neuromuscular diseaseApo E and neuromuscular disease
ApoE e4 association with an increased risk for ApoE e4 association with an increased risk for developing and faster progression of certain developing and faster progression of certain
neuromuscular diseases, while neuromuscular diseases, while
ApoE e2 may have the protective effect and is ApoE e2 may have the protective effect and is associated with better prognosis for neuromuscular associated with better prognosis for neuromuscular
diseases such as motor neuron disease. diseases such as motor neuron disease.
The effect of various APOE alleles on neuromuscular The effect of various APOE alleles on neuromuscular diseases therefore parallels their influence on diseases therefore parallels their influence on
central nervous system diseases.central nervous system diseases.
Bedlack, Strittmatter, Morgenlander. Arch Neurol 2000 57: 1561-5.
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
Cholesterol and Receptor functionCholesterol and Receptor functionnAChR nAChR
Reviewed by Naguib et al, Anesthesiology 2002Reviewed by Naguib et al, Anesthesiology 2002
GABAGABAAASooksawate and Simmond, Neuropharmacology, 2001, Br J Pharm 2001Sooksawate and Simmond, Neuropharmacology, 2001, Br J Pharm 2001
5HT1A5HT1AScanlon, Williams, Schloss. Biochemistry 2001Scanlon, Williams, Schloss. Biochemistry 2001
Scalzitti et al. Society for Neurosci Abstract 2003, Scalzitti et al. Society for Neurosci Abstract 2003, available at Neurobiology of Lipids, Vol. 2, 3available at Neurobiology of Lipids, Vol. 2, 3
GlyRGlyRLaube. Society for Neurosci Abstract 2003, Laube. Society for Neurosci Abstract 2003, available at Neurobiology of Lipids, Vol. 2, 3available at Neurobiology of Lipids, Vol. 2, 3
Excitatory Amino Acid TransportersExcitatory Amino Acid TransportersButchbach, Guo, Lin. Society for Neurosci Abstract 2003, Butchbach, Guo, Lin. Society for Neurosci Abstract 2003,
available at Neurobiology of Lipids, Vol. 2, 3available at Neurobiology of Lipids, Vol. 2, 3http://neurobiologyoflipids.org/content/2/3http://neurobiologyoflipids.org/content/2/3
Koudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7
TAKE HOME MESSAGETAKE HOME MESSAGE
Cholesterol itself plays essential role in the mechanisms of synaptic function, plasticity and
neurodegeneration
Central neurodegeneration features in a
number of neurodegenerative diseases
may represent functional consequences
of abnormal neural cholesterol
misregulation
KOUDINOVSKoudinova et al: Cholesterol failure is a unifying cause of neurodegeneration
Neurobiology of Lipids, 2004, Vol. 3, 7, http://neurobiologyoflipids.org/content/3/7