Diapositiva 1

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LA MEDICINA DEL DOMANI INVECCHIARE CON
SUCCESSO Presidente Prof. P.Marandola MEDICINA
ANTI-AGING FROM BENCH TO BEDSIDE Presidente
Prof. C.Caruso
San Alessio Siculo, 6-7 Dicembre 2007
Omocisteina e malattie neurodegenerative
Riccardo Ientile Dipartimento di Scienze
Biochimiche Fisiologiche e della
Nutrizione Universita di Messina
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Homocysteine in Neurodegenerative Disorders
Examples of molecular cascades induced by
homocysteine that can lead to cell dysfunction
and/or death in cardiovascular disease, and
neurodegenerative diseases
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Homocysteine metabolism
Folate
Methionine
Dihydrofolate (FH2)
Methionine adenosyltransferase
S-Adenosylmethionine
Tetrahydrofolate (FH4)
Acceptor
Methyl transferase
MTR,Vit.B12
Methylated Acceptor
5, 10-Methylene FH4
S-Adenosylhomocysteine
MTHFR
Adenosine
5-Methyl FH4
Homocysteine
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J Alzheimers Dis. 2006 Aug9(4)393-8. Elevated
plasma homocysteine levels risk factor or risk
marker for the development of dementia and
Alzheimer's disease? Seshadri S. Department of
Neurology, Boston University School of Medicine,
715 Albany Street B-608, Boston, MA 02118, USA.

• ... Epidemiological studies have confirmed that
  elevations in plasma tHcy temporally precede the
  development of dementia and that there is a
  continuous, inverse linear relation between
  plasma tHcy concentrations and cognitive
  performance in older persons.

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Association of IMT, Hcy plasma levels and C677T
SNP with cognitive status in AD and MCI

• 45 pazienti con AD (22M/23F 77,4 7,6 aa)
• 18 con MCI (8M/10F 71 9,8 aa )
• 63 controlli non dementi (32M/31F 76,6 10,2 aa)

CRITERI DI INCLUSIONE Diagnosi di AD
probabile secondo i criteri NINCDS-ADRDA o di
MCI secondo Petersen. Anamnesi
negativa per tabagismo, abitudine al potus,
ipotiroidismo, neoplasia, malassorbimento
Anamnesi negativa per disordini
vascolari maggiori Non uso di farmaci o
vitamine che influenzano i livelli di omocisteina
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RISULTATI
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RISULTATI
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Studio di correlazione omocisteina plasmatica
Mini Mental State Evaluation
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REGRESSIONE MULTIPLA
Variabile indipendente MMSE ( valori ln
trasformati)
R 0,6 R2 0,4 observed power 0,83
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CONCLUSIONI
Livelli di Hcy correlano con il declino
cognitivo
Associazione significativa tra presenza genotipo
TT677 del gene MTHFR e declino cognitivo.
Evidenze di un possibile ruolo dellaterosclerosi
nello sviluppo del declino cognitivo in pazienti
con Malattia di Alzheimer
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Adverse effects of folate deficiency and
homocysteine in neurons
Abbreviations NAC, N-acetylcysteine PARP,
poly-(ADP-ribose)-polymerase SAM,
S-adenosylmethionine.
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Impaired transmethylation of DNA
Methylation of presenilin
ER stress
ß-Amyloid
NMDA-R
Ca2 influx to cytosol
Enzymes
Externalized PS PARP
NOS PLA2 LOXCOX
Free radicals
Neurological disorders
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Homocysteine as a neurotoxin
is excitotoxic increases oxidative stress
promotes apoptosis
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ROS
Classical pathway of NF-?B activation
NEMO
NEMO
IKKb
IKKa
p50
p65
p50
p65
Under appropriate stimuli NF-?B translocates to
the nucleus where is able to exert positive or
negative control over cell gene transcription
p50
p65
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NF-?B DNA binding activity in nuclear extracts of
Hcy-treated Neuro2a cells
A supershift analysis, which was carried out by
incubating nuclear proteins with specific
monoclonal antibodies against p50 and p65 NF-?B
subunits, demonstrated that NF-?B activated
complexes were p50/p65 heterodimers.
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The role of NF-kB activation can be evaluated
using a specific inhibitor of NF-kB nuclear
translocation
SN50
p50
p65
1AAVALLPAVVLLAPVQRKRQKLMP26 SN-50 (Lin et
al., 1995) Membrane-translocating hydrophobic
sequence p50 nuclear localization sequence
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Homocysteine triggers the activation of
apoptotic machinery in neuroblastoma cells
p53
Caspase 3
CLSM
Control
Hcy (250 µM)
p53
51 k gt
Ctr
Hcy SN-50
Hcy
Hcy-induced increases in p53 and caspase 3
expression
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Hcy induces the ER stress response
Herp
Homocysteine
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Putative mechanisms of homocysteine effects
Hcy induced the ER stress response leading to
the expression of Hcy-induced ER protein (Herp).
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Homocysteine induced the ER response
HCY
CYS
Herp expression
TG2 IN SITU ACTIVITY
CASPASE 3 EXPRESSION
TG2 EXPRESSION
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Protein aggregates induces ER stress
Insoluble aggregates
tTG, Ca
ER
Apoptosis
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Take home message
Alteration of redox status triggered by Hcy may
affect NF-?B nuclear translocation.
The Hcy-induced effects are dependent on ER
stress.
Further studies should be carried out to
characterize protein mysfolding following
Hcy-induced ER stress.
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P.M. RossiniUniversità Campus Bio-Medico di Roma
F. PisaniClinica NeurologicaUniversità di
Messina
P. CalabresiClinica Neurologica, Università di
Perugia
Daniela Caccamo Salvatore Condello Monica Currò
Nadia Ferlazzo Gaetano GorgonePatrizia
ImpalàGiorgio Loccisano Giulia Parisi
.Thank you for your attention