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Global Health Conference FIU Miami May 7-9, 2019Familial Alzheimer’s Disease as a research model for Alzheimer’s: A pathological perspective
Dr. Med. Diego Sepulveda-FallaMoNeA - Gruppenleiter
Institut für Neuropathologie , Molecular Neuropathology of Alzheimer‘s Disease - MoNeA
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β Amyloid Plaques
Neurofibrillary Tangles
Auguste D
Alzheimer’s Disease
http://static.ow.ly/photos/original/3XGlP.jpg
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http://www.discoverdevelopment.com/Images/gamma-secretase.png
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FAD vs SAD
Sepulveda-Falla D et al. J Alz Dis, 2012
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Aβ in FAD
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pTau in FAD
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TDP43 in FAD
Phospho TDP 43
SAD FAD
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de novo generation of Aβ in PS1E280A brain tissue
(Modified from Szaruga et al. J Exp Med, 2015) (Mod
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(Modified from Sepulveda-Falla D et al. J Clin Invest, 2014)
Cerebellar dysfunction in PS1E280A FAD
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Mitochondrial dysfunction in PS1 mutations
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Differences between Sporadic and Familial Alzheimer’s Disease
Phenotype SAD PS1-FADBeta Amyloid Pathology
Increased Beta Amyloid 1-42
Cerebellar Beta Amyloid pathology
Cerebellar symptoms
Increased IDE in plaques
Neprylisin in plaques
Hyperphosphorylated Tau Pathology
Cerebellar pTau pathology
Elevated BACE1 levels
Increased beta APP-CTF levels
Increased Purkinje cells loss
Cerebellar abnormal mitochondria
Dysregulation of Ca2+ channels
γ-secretase dysfunction
Increased Beta Amyloid 1-38 (IHC)
Increased 38/42 ratio (IHC)
Increased 40/43 ratio (IHC)
Increased 42/40 ratio (IHC)
TDP43 Pathology (IHC)
Increased insoluble pTDP43
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Aβ pathology according to age of onet in PS1E280A FAD
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pTau pathology according to age of onet in PS1E280A FAD
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1. Are SAD and FAD the same disease?
Phenotype SAD PS1-FADBeta Amyloid Pathology
Increased Beta Amyloid 1-42
Cerebellar Beta Amyloid pathology
Cerebellar symptoms
Increased IDE in plaques
Neprylisin in plaques
Hyperphosphorylated Tau Pathology
Cerebellar pTau pathology
Elevated BACE1 levels
Increased beta APP-CTF levels
Increased Purkinje cells loss
Cerebellar abnormal mitochondria
Dysregulation of Ca2+ channels
γ-secretase dysfunction
Increased Beta Amyloid 1-38 (IHC)
Increased 38/42 ratio (IHC)
Increased 40/43 ratio (IHC)
Increased 42/40 ratio (IHC)
TDP43 Pathology (IHC)
Increased insoluble pTDP43
2. Have all FAD (or even all PS1 FAD) the same pathology?
3. At least are all E280A cases the same from a pathological point of view?
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DeathBirth
APP Processing Dysfunction
Metabolic Dysfunction
Inflammation / Immunity
Homeostasis / Turnover
EnvironmentAβ Pathology
pTau Pathology
Cognitive impairment
NeurodegenerationPrimary
Secondary
Endp
oint
Pat
holo
gy
?
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Acknowledgements
Colombia University of Antioquia
Brain Bank teamAndres VillegasFrancisco LoperaJorge Ivan VelezClaudio MastronardiMauricio Arcos-Burgos
Germany University of Hamburg
*Alvaro Barrera-Ocampo*Liliana Rojas-Charry *Sergio Calero-Martinez*Marcus Broeckmayer*Tim VersteegenBerta Puig*Felix DinkelBeata SzalayMarkus GlatzelDiagnostic team
BelgiumKU Leuven
Lucia Chavez-Gutierrez Bart de Strooper
SwedenUniversity of Gothenburg
Erik PorteliusKaj Blennow
SpainUniversity of Barcelona
Isidro Ferrer
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Gracias !