The Search for Medecine for Down s syndrome

The Search for Medecine for Down’s syndrome
Wellcome Trust Conference Centre
Therapeutical Approach for common clinical aspects in Trisomy 21 and Alzheimer disease
J. LONDON
September 17th 2011 Genome Campus, Hinxton, Cambridge, UK

Early Alzheimer disease (AD) and trisomy 21(I)
• Diminution of some brain areas • Loss and abnormal structure of synapses • Disturbed axonal and dendritic remodeling • Diminution and altered morphology of dendritic
spines • Loss of functional connectivity between frontal and
parietal cortices • Abnormal hippocampic and cerebellum
neurogenesis • Cholinergic circuity deficits • MRI abnormalities • cognitive deficits • Spatiotemporal abnormalities • poor smelling • sleep disturbancy • agraphia, dysgraphia

Gene and risk factors for AD in T21 persons (II)
• Many chromosome 21 genes may be involved : APP, S100beta, BACE2, SOD1, Dyrk1A, DSCR1, ApoE e4
• SOD1 : deleterious or protective? • CBS (related to homocystein) ?? • Abnormal APP metabolism : Measurements of Ab40, 41 and 42 and activities of secretases
(Nistor M. et al. Neurobiol. of aging 2007; Mehta et al2009)

Alzheimer disease (AD) and trisomy 21(III)
- Conversely to the assumption that all T21 persons will develop AD, dementia is not really more frequent in the DS population than in the old general population but occurs earlier and the course of the dementia is shorter, although the biochemical and physiological hallmarks are present very early!!!
BUT - Some of the deficits listed above are present: - during early childhood in DS persons - early in the course of the disease in AD patients
Thus - Pharmacological intervention to decrease these deficits in DS may help to understand better early deficits in AD - Finding some therapy for AD persons may help DS persons!!

Alzheimer disease (AD) and trisomy 21(IV)
Questions
• Is the AD type neuroanatomo-histopathology one of the cause of cognitive deficit ?
• Why there is no dementia before 40-50 years old? Is the vascular protection in DS involved??
• Why, despite the presence of these hallmarks only 40% of the DS persons will develop dementia?
Roles of DyrK1A overexpression in AD and DS
• induces cognitive deficits in mice • Leads to abnormal morphogenesis and neurogenesis • Alters synaptic plasticity anbd memory consolidation • Is overexpressed in DS and AD brain • Phosphorylates Tau and APP • These deficits in mice can be reversed by Dyrk1A inhibition

Aim of this talk
• Demonstrate that the clinical trials using EGCG or another compound which will be going on for cognitive improvement, might be beneficial for some of the other DS aspects such as: sleep and olfactive impairments, skin and hair problems, obesity, diabetes, anxiety and general aging.
• Some of these aspects are important for day-life and might be more easily evaluated than cognitive functions

EGCG
Epigallocatechin-3-gallate

Epigallocatechin gallate (EGCG) 1. Neurology 2. Sleep 3. Olfaction 4. Hair and Skin 5. Others: Obesity, anxiety, aging,diabetes

1. Neurology
A) Neurogenesis
• Neuroprotective molecular mechanisms of (-)-epigallocatechin-3-gallate: a reflective outcome of its antioxidant, iron chelating and neuritogenic properties (Weinreb O. Genes Nutr. 2009) • Epigallocatechin-3-gallate protects motor neurons and regulates glutamate level. (Yu J, FEBS Lett. 2010)
• Dual beneficial effects of(-)-epigallocathechin-3-gallate on levodopa methylation and hippocampal neurodegeneration : in vito and in vivo studies (Kang KS, Plosone 2011)
• APP induces fundamental gliocentric shift in the progenitor pool that impairs neuronal production(Lu J., Plosone, 2011)

C) EGCG and APP metabolism
• Reduces APP cleavage and cerebral amyloidosis in Tg mice (Rezai-Zadeh K. 2005)
• Induce αsecretase cleavage of APP (Obregon DF et al 2006)
• Is a potential strategy for AD (Youdim BH 2008 and 2010)
• Remodels mature amyloid β fibrils and reduces cell toxicity (Bieschke 2010)
• Nanolipidic particles of EGCG improve bioavailability by inducing asecretase for the treatment of AD ( Smith A. 2010)