1. Designing drugs for neuroprotection
Dr Gayle H Doherty
School of Psychology and Neuroscience, University of St Andrews

2. Cost: $100-300 million 5-7 yrs 2yrs The Drug Discovery Process
Target identification
Target validation
Lead identification
Candidate optimization
Pre-clinical Testing
Animal trials
Toxicity and pharmaco-kinetics
Clinical Testing
Phase I
Phase II
Phase III
Approval
Phase IV
5-7 yrs
2yrs
Cost: $ million

3. Drug repurposing – new jobs for old drugs
High
New chemicals:
>10yrs to develop
>$100 million
2% success
Risk
Repurposing:
2 yrs to develop
$2-10 million
25% success
Low
Low
High
Return

4. Risk factors for Alzheimer’s disease
Leptin
Age Leptin levels decrease with age
Family history No established link to leptin
Head trauma Leptin benefits healing after head trauma, therefore…
Low education No link to leptin levels
Mid-life hypertension ?
Depression Leptin levels reduced, especially women
Smoking Leptin levels reduced
Inactivity Leptin levels reduced
Mid-life obesity Leptin levels reduced/ leptin insensitivity
Diabetes Leptin levels reduced/ leptin insensitivity

5. Leptin Anti-obesity hormone Control food intake BUT
Also has a lot of other functions in the brain
Keeps neurons alive
Helps them to signal to one another

6. Can leptin protect neurons?
Doherty et al., Neurobiol. Aging, 2013

7. Can leptin prevent AD pathology?
Tangles = build up of p-tau
Other markers – increased
expression of endophilin 1

8. Leptin prevents upregulation of p-tau and endophilin 1 in vitro
1 = control
2 = Ab1-42
3 = 100nM leptin
4 = Ab1-42 +
100nM leptin
Doherty et al., Neurobiol. Aging, 2013

9. Zucker Fa/fa and fa/fa rats
Not genetically manipulated
Spontaneous null mutaion of ob receptor
Obesity by 4 weeks of age
Memory deficits by 6 months of age
Biochemistry of brain unknown

10. What about animals that don’t respond to leptin?
Doherty et al., Neurobiol. Aging, 2013

11. Can leptin protect neurons?
Yes
Very few tau tangles
Lots of tau tangles

12. Why would leptin be a good drug?
It counteracts AD pathology at multiple levels
Already licensed to fight obesity in humans
Well tolerated – it is a naturally occurring hormone

13. Why wouldn’t leptin be a good drug?
Very big molecule
Hard to administer
Cost

14. What now?

15. Leptin (116–130) prevents copper and Aβ-induced cell death in human SH-SY5Y cells.
Leptin (116–130) prevents copper and Aβ-induced cell death in human SH-SY5Y cells. (A) Pooled data revealing that leptin and leptin (116–130) prevent LDH release induced by administration of 5 μM CuCl2. (B) Similar pooled data was obtained for cultures treated with 10 μM Aβ1–42. (C) Pooled data showing that in 5 μM CuCl2 treated cultures enhanced numbers of cells are detected with a crystal violet assay when cultures are cotreated with either leptin or leptin (116–130) with a similar trend observed when cultures were induced to die with 10 μM Aβ1–42 (D).
Yasaman Malekizadeh et al. Cereb. Cortex 2016;cercor.bhw272
© The Author Published by Oxford University Press. All rights reserved. For Permissions, please

16. Leptin (116–130) enhances episodic-like memory.
Leptin (116–130) enhances episodic-like memory. (A) Object–place–context task used to assess episodic-like memory. There are 2 sample phases in which mice are exposed to different copies of 2 different objects (star and hexagon) and allowed to explore for 3 min. In the test phase they see 2 new copies of 1 of the objects. The arrow points to the object that has not been previously seen in that place within that context. (B) Mean ± SEM discrimination index for the 3 groups. *P < 0.05. (C) Total exploration time in the test phase is not different between groups. (D) Exploration of the novel and familiar objects in the test phase.
Yasaman Malekizadeh et al. Cereb. Cortex 2016;cercor.bhw272
© The Author Published by Oxford University Press. All rights reserved. For Permissions, please

17. Conclusions
Leptin(116–130) mirrored the cognitive enhancing effects of leptin as it enhanced performance in episodic-like memory tests.
Leptin(116–130) prevented hippocampal synaptic disruption (not shown)
Leptin(116–130) neuronal cell death in models of amyloid toxicity.
These findings establish further the importance of the leptin system as a therapeutic target in AD.

18. With Thanks With Thanks University of Dundee University of St Andrews
Dayne Becanno-Kelly
Jenni Harvey
With Thanks
University of St Andrews
Vanya Metodieva
Lisa Strother
Alison Holiday
Laidlaw Undergraduate
Internship Programme
University of St Andrews