Alzheimer's disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, as well as changes in behavior and personality AD pathology is characterized by the formation of two types of protein aggregates in the brain: amyloid plaques — which form an extracellular lesion composed of the Aβ peptide; and intracellular neurofibrillary tangles) — which are composed of hyperphosphorylated filaments of the microtubule-associated protein tau. AD is also associated with inflammatory responses, synaptic damage, changes in hormonal levels, and mitochondrial structural and functional abnormalitie. the molecular events leading to synaptic loss in AD are unknown

1. RNA silencing of genes involved in Alzheimer's
disease enhances mitochondrial function and
synaptic activity.
Presented by
Razieh mohamadian
Supervisor
Dr . Ardestani

3. Introduction

4. History of Alzheimer's disease (AD)
Alzheimer’s disease was first discovered in 1906
by a German neurologist,
Dr. Alois Alzheimer (1864-1915).
A 51 year old woman died from a
“mental illness.”
She suffered from depression, paranoia,
hallucinations, and dementia.
Dr. Alzheimer examined her brain & found:
“peculiar formations”  amyloid plaques
“dense bundles”  neurofibrillary tangles

5. Alzheimer's disease (AD)
• Alzheimer's disease (AD) is the most common cause of mental dementia in
the aged population.
• AD is characterized by the progressive decline of memory and multiple
cognitive functions, as well as changes in behavior and personality
• AD pathology is characterized by the formation of two types of protein
aggregates in the brain: amyloid plaques — which form an extracellular
lesion composed of the Aβ peptide; and intracellular neurofibrillary tangles)
— which are composed of hyperphosphorylated filaments of the microtubule-
associated protein tau.
• AD is also associated with inflammatory responses, synaptic damage,
changes in hormonal levels, and mitochondrial structural and functional
abnormalitie.
• the molecular events leading to synaptic loss in AD are unknown.

6. 22

7. Types of Alzheimer’s
There are 3 types of
Alzheimer’s
Familial Alzheimer’s
disease (FAD)
Early-onset
Alzheimer’s
Late-onset
Alzheimer’s

8. Stages of Disease

9. therapeutic strategies

10. AD related genes
• increased expression levels of AD-related genes have been
associated with the progression of AD
• These genes include VDAC1, ANT, CypD, APP, PS1, BACE1, and
Tau
• recent genetic studies have revealed that the increase or
duplication of the APP gene is toxic to the human brain and is
sufficient to cause AD.
• the reduction of gene expressions associated with AD may be
responsible for the reduction of toxic accumulations of Aβ and
phosphorylated Tau, resulting in the slowing of AD progression.
• In studies of RNA silencing (siRNA) in AD, researchers silenced AD
genes

11. Purpose of study
• 1) the effects of RNA silencing of APP, Tau, and VDAC1 genes on
mRNA levels in studies of genes related to synapses, mitochondria,
and AD .
• 2) mitochondrial function in RNA-silenced APP, Tau, and VDAC1
genes by measuring free radical production, lipid peroxidation,
cytochrome oxidase activity, ATP production, and GTPase
enzymatic activity

12. amyloid precursor protein (APP)

13. tau protein

14. voltage-dependent anion channel 1
(VDAC1)

15. Material & Methods
• Materials
human neuroblastoma (SHSY5Y) cells
human APP gene
human Tau gene
VDAC1 gene
• Methods
RNA silencing of human APP, Tau, and VDAC1 genes
Real-time RT-PCR analysis
Immunoblotting analysis
Statistical analysis for mitochondrial functional parameters

16. RNA silencing

18. mRNA fold changes of mitochondrial, synaptic,
and AD-related genes in SiRNA–APP,tau,VDAC1

19. Immunoblotting analysis of SiRNA-APP, SiRNA-Tau,
and SiRNA-VDAC1

20. Mitochondrial Function in SiRNA-APP Cells

21. Mitochondrial Function in SiRNA-Tau cells

22. Mitochondrial Function in SiRNA-VDAC1 Cells

23. Discussion
reduction of APP, Tau, and VDAC1 genes is likely to
increase synaptic activity and enhance mitochondrial
function and reduced expressions of several AD-related
genes.
But How?!

24. Aβ
• APP and Aβ
• induce excessive amounts of free radical production
• reduce cytochrome oxidase activity
• inhibit ATP production
• the interaction of Aβ with CypD, ABAD, Drp1
• forms abnormal complexes…
These complexes are critically
responsible for mitochondrial
dysfunction, defective
mitochondrial axonal transport,
and synaptic damage in AD
neurons.

25. VDAC1-Aβ complex

26. Tau hyperphosphorilation
Hyperphosphorilated Tau
&
Nfts

27. conclusions
• SHSY5Y cells with mRNA silenced APP, Tau, and VDAC1 exhibited
• increased synaptic gene expressions
• enhanced mitochondrial function,
• and reduced GTPase Drp1 enzymatic activity
all of which are known to be beneficial for synaptic activity and
mitochondrial function.

28. Kindness is mark of faith and whoever
is not kind has no faith
(prophet muhammad)
There is one thing alzheimer's
can not take away, and that is
LOVE…
Thanks for your attention