RNA silencing of genes involved in Alzheimer's disease enhances mitochondrial function and

synaptic activity.

Presented by Razieh mohamadian

SupervisorDr . Ardestani

Introduction

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

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.

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Types of Alzheimer’s

There are 3 types of Alzheimer’s

Familial Alzheimer’s disease

(FAD)

Early-onset Alzheimer’s

Late-onset Alzheimer’s

Stages of Disease

therapeutic strategies

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

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

amyloid precursor protein (APP)

tau protein

voltage-dependent anion channel 1 (VDAC1)

Material & Methods • Materialshuman neuroblastoma (SHSY5Y) cells human APP genehuman Tau geneVDAC1 gene• MethodsRNA silencing of human APP, Tau, and VDAC1 genes Real-time RT-PCR analysisImmunoblotting analysisStatistical analysis for mitochondrial functional parameters

RNA silencing

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

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

Mitochondrial Function in SiRNA-APP Cells

Mitochondrial Function in SiRNA-Tau cells

Mitochondrial Function in SiRNA-VDAC1 Cells

Discussionreduction 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?!

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.

VDAC1-Aβ complex

Tau hyperphosphorilation

Hyperphosphorilated Tau&

Nfts

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.

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