1. AlzForum Webinar 9/29/11 – Ralph Nixon!
• Balance (not redirect) AD research portfolio:!
Alzheimerʼs – a multifactorial disease!
Other neurodegenerative diseases can inform
AD drug development!
AD genetics support additional pathogenic
mechanisms relevant to therapy!
• The cost of future amyloid therapy trials, especially
prevention trials, should be weighed against that of
validating a wider range of targets.!

2. The Endosomal-Lysosomal Network: Genetic Hotspot in
Neurodegenerative Disease Pathogenesis?!
• AD- App, ApoE ε4, SORL1, ?pCALM!
EE!
• ALS- Alsin !
• Huntington s disease- Htt/HAP40 complex !
• Frontotemporal Dementia - CHMP2B, p97/VCP!
LE!
• Hereditary Spastic Paraplegia- Spg4 (Spastin),
• ALS - p97/VCP! !and Spartin!
• Parkinson s Disease- Pink, Parkin! • Charcot-Marie Tooth Type 2B - rab 7, FIG4,
!and SH3TC2!
• ALS – CHMP2B!
PAS! AP! !
AL !
Lyso
• Parkinson s Disease - ATP 13A2!
• Lysosomal Storage Diseases (juvenile/adult forms)
! • AD - Presenilin 1, Psen2, cystatin C!
• Niemann-Pick Type C!
• Mucopolysaccharidosis IIIB!
• Gaucher s Parkinson s!
• Chediak-Higashi PD/Dementia!
• Neuronal Ceroid Lipofuscinosis!
Not shown are many neurodevelopmental disorders caused by genes regulating the lysosomal network!

3. Therapeutic targeting of autophagy in AD mouse models!
Rapamycin"
Caccamo et al., 2010!
Spilman et al., 2010!
Ravikumar et al., 2004!
Fornai et al., 2008!
Crippa, 2010!
Cystatin B KO"
AMPK! Resveratrol" Yang et al., 2011!
Curcumin" Vingtdeux et al., 2011! Cystatin C KO"
Lithium" mTOR! Cystatin C" Sun et al., 2008!
Resveratrol" Tizon et al., 2010!
Caloric restriction"
Increase cathepsin activity"
BECN expression" Mueller-Steiner et al., 2006!
SIRT1" Spencer et al., 2009!
Butler et al., 2011!
Isolation Membrane! AP! AL! Lyso!
SMER28"
Tian et al., 2011!
Trehalose"
Aguib et al., 2009!
Rodriguez-Navarro, 2010!
In AD mouse models, reduces:! Therapeutic effects in other disease models*:!
1) Amyloidosis! Synucleinopathy!
2) Tauopathy! Parkinson s disease!
3) Cytotoxicity! Lewy body disease!
4) Synaptic Impairments! ALS, !
5) Cognitive Impairment ! Prion infection!

4. AD-related genes drive endosomal-lysosomal dysfunction and
consequent pathogenesis by both Aß-independent and dependent
mechanisms !
App gene duplication! Impaired NGF transport!
APP mutation! βCTF-rab5
Defective endocytic signaling!
ApoE ε4! EE! Cholinergic neurodegeneration!
!
SORL1/LR11 βCTF/Aβ overproduction!
LRP/Cholesterol! Impaired endocytic transport!
Impaired endo/lyso transport and!
LE! !Aβ/βCTF clearance!
AL!
Presenilin 1!
Presenilin 2! Decreased Aβ clearance!
Cystatin C! AP! Altered tau cleavage!
Neuritic dystrophy!
Cathepsin leakage!
Lyso!
Apoptosis/necrosis!
Isolation
Membrane! Ihara et al. 2011, in press!
The Biology of Alzheimer Disease. Selkoe D, Holtzman D, Mandelkow E (Eds.).

5. AlzForum Webinar 9/29/11 – Ralph Nixon!
• Balance (not redirect) AD research portfolio:!
Alzheimerʼs – a multifactorial disease!
Other neurodegenerative diseases can inform
AD drug development!
AD genetics support additional pathogenic
mechanisms relevant to therapy!
• The cost of future amyloid therapy trials, especially
prevention trials, should be weighed against that of
validating a wider range of targets.!