Alzheimer's disease

ALZHEIMER'S DISEASE

(AD)

Jinnah University for Women

INTRODUCTION &

HISTORY OF ALZHEIMER'S

DISEASE

INTRODUCTION

Alzheimer – neurological disorder in which the

death of brain cells and shrinkage of brain causes

memory loss and cognitive decline.

Disease starts mild and gets progressively worse.

Besides memory loss, Alzheimer's patients show;

Dramatic personality changes,

Disorientation,

Declining physical coordination, and

Inability to care for themselves.

Leading cause of neurodegenerative type of

dementia (memory loss).

INTRODUCTION

Leading cause of death in developed nations.

AD victims – dies of infection secondary to AD

(usually pneumonia & UTIs).

AD is much more prevalent in women.

AD probably results from the inflammatory

response induced by extracellular Aβ deposits,

which later become enhanced by aggregates of tau.

Genetic defect in chromosome 21 – leads to AD.

INTRODUCTION

Diagnosed – by the presence of amyloid plaque &

neurofibrillary tangles.

Incurable – leads to death with avg of 8 years after

diagnosis.

The last 3 of which are typically spent in an

institution.

In final stages, victims are confined to bed with lose

urinary and bowel control.

HISTORY

Alois Alzheimer when, in November 1907,

reported – an unusual illness of the cerebral

cortex).

His paper gives a brief description of the clinical

history in a case of dementia with onset at age

51 and the unique pathological findings of

plaques and tangles.

The failure to pay much attention to this

hallmark paper continued for a further seven

decades.

HISTORY

The decade from 1982 to 1992 was a

groundbreaking era for unraveling the mysteries of

AD.

Up to then, age was the only known risk factor.

Below age 65 AD was found to be rare.

There was no explanation then, nor is there now, as

to why age is so critical.

AMYLOID CASCADE

HYPOTHESIS

AMYLOID CASCADE HYPOTHESIS

The amyloid cascade hypothesis is widely accepted

as the centerpiece of Alzheimer disease (AD)

pathogenesis.

Proposes that key event leading to AD – formation

of amyloid beta (beta amyloid, Aß).

Aß clusters into amyloid plaques – on the blood

vessels and on the outside surface of neurons –

ultimately leads to the killing of neurons.

AMYLOID PRECURSOR PROTEIN (APP).

The amyloid beta peptide is created by enzyme

cleaving of the normal neuron membrane protein

known as Amyloid Precursor Protein (APP).

Natural neuro-protective agent.

Cleaved by various types of secretases such as α,

β and γ.

APP

α secretase

No Aßformation

No amyloidclump

β secretase

γsecretase

Cleavage on trans-Golgi

network

Aß 40(mostly

harmless & soluble)

Cerebrovascular plaques

Cleavage on E.R

Aß 42(insoluble &

clumps together)

NeuriticAmyloid plaque

cleavage

Cleavage Of Amyloid Precursor Protein

DEATH OF NEURONS

Following amyloid

plaque formation two

processes play an

important role in

causing the death of

neurons:

1. Inflammation and

oxidative damage,

and

2. NeuroFibrillary

Tangles (NFTs).

INFLAMMATION AND OXIDATIVE DAMAGE

The two major types of brain cells that participate inthe inflammatory response are astrocytes &microglia. Produces damaging free radicals and lead to the death of

neurons.

Oxidative damage to DNA – caused by reactiveoxygen species (ROS)

produced by irradiation or by metabolic bi-products.

Most prominent biomarker of oxid8ative damage is8-oxo-hydroxyoxyguanosine.

Levels of 8-OHdG are 18 times higher in CSF ofAlzheimer's Disease individuals than normal.

NEUROFIBRILLARY TANGLES (NFTS).

Tau – important protein that stablizesmicrotubules of neurons by binding tothem.

But in AD the tau proteins becomehyper-phosphorylated – lose thecapacity to bind to microtubules ofbrain cells.

The phosphorylated tau proteins - bindto each other, tying themselves in"knots" known as NeuroFibrillaryTangles (NFTs).

Neurons full of NFTs rather thanfunctional microt ubules soon die.

CASCADE

APP

Aß42

Amyloidplaques

Inflammation, oxidative damage and NFTs

Neuron death

ALZHEIMER'S DISEASE

GENETICS

ALZHEIMER'S DISEASE GENETICS

Alzheimer's disease is anirreversible, progressive braindisease.

It is characterized by thedevelopment of amyloid plaquesand neurofibrillary tangles, the lossof connections between nervecells, or neurons, in the brain, andthe death of these nerve cells.

There are two types of Alzheimer's-early-onset and late-onset. Bothtypes have a genetic component

EARLY-ONSET ALZHEIMER'S DISEASE

Early-onset Alzheimer's disease occurs in people

age 30 to 60.

It is rare, representing less than 5 percent of all

people who have Alzheimer's.

Most cases are inherited, a type known as familial

Alzheimer's disease (FAD).

Familial Alzheimer's disease is caused by any one

of a number of different single-gene mutations on

chromosomes 21, 14, and 1. Each of these

mutations causes abnormal proteins to be formed.

These mutations plays a role in the breakdown ofAPP – generates harmful forms of amyloidplaques, a hallmark of the disease.

A child whose mother or father carries a geneticmutation for FAD has a 50/50 chance of inheritingthat mutation.

Mutations

Chromosome 21

Abnormal amyloid

precursor protein (APP).

Chromosome 14

Abnormal presenilin 1 to be

made,

Chromosome 1

Abnormal presenilin 2

formation

LATE-ONSET ALZHEIMER'S DISEASE

Most cases of Alzheimer's are the late-onset form i.edevelops after age 60.

Causes – not yet completely understood,

But they likely include a combination of

genetic,

environmental, and

lifestyle factors

that influence a person's risk for developing the disease.

Single-gene mutations – not seem to be involved in late-onset Alzheimer's.

Researchers have not found a specific gene that causesthe late-onset form of the disease.

However, one genetic risk factor does appear toincrease a person's risk of developing the disease.


This increased risk is related to the apolipoprotein E

(APOE) gene found on chromosome 19.

APOE makes a protein that helps carry cholesterol and

other types of fat in the bloodstream.

APOE comes in several different forms, or alleles.

Three forms occur most frequently

1. APOE ε2,

2. APOE ε3,

3. APOE ε4

APOE ε2 is relatively rare and may provide some

protection against the disease. If Alzheimer's disease

occurs in a person with this allele, it develops later in life

than it would in someone with the APOE ε4 gene.


APOE ε3, the most common allele – play a neutral role

in the disease – neither decreasing nor increasing risk.

APOE ε4 is called a risk-factor gene because it

increases a person's risk of developing the disease.

APOE ε4 is present in about 25 to 30 percent of the

population and in about 40 percent of all people with

late-onset Alzheimer's. People who develop Alzheimer's

are more likely to have an APOE ε4 allele than people

who do not develop the disease.

However, inheriting an APOE ε4 allele does not mean

that a person will definitely develop Alzheimer's.

METAL TOXICITY & FREE

RADICALS

METAL TOXICITY & FREE RADICALS

Epidemiological studies -- indicated a correlation of

aluminum in drinking water with the prevalence of

AD,

Whereas studies of aluminum occupational

exposure and aluminum in antacids have shown no

correlation

Aluminum concentration is elevated in NFTs &

amyloid plaques, but this may be an effect of AD

rather than a cause.

Mercury is also elevated in the AD brain.


Zinc, copper & iron — all of which are enriched in

amyloid-beta plaques in AD.

All three metals lead to Aß aggregation, but

chelation can completely reverse metal-induced

precipitation of Aß

Copper particularly mediates Aß toxicity, whereas

zinc inhibits toxicity

Aß is not toxic to neurons in the absence of Cu2+

Aß converts Cu2+ and Fe3+ to Cu+ and Fe2+, both of

which generate free radicals.


Fe3+ induces aggregation of phosphorylated NFTs,

but this aggregation can be reversed by reducing

Fe3+ to Fe2+

Copper & iron in these plaques generate hydrogen

peroxide leading to oxidative damage.

Membranes containing oxidatively damaged

phospholipids also promote amyloid ß-sheet

formation


Amyloid-beta aggregation by acidic conditions and

by copper, iron, zinc & aluminum results - the highly

toxic ß-sheets.

Copper binds more strongly to Aß42 than to Aß40

and copper is a greater catalyst of free radical

formation than are the other metals

DISCUSSION

DISCUSSION

AD not gained universal support, for more than 20

years – since the amyloid cascade hypothesis was

first put forward.

Because of many unsuccessful attempts to develop

disease-modifying treatments.

One problem – failure to recognize that it is the

inflammatory response to Abeta deposits, and later

cortical tau aggregation, which drives the

pathology.

Etiology and pathogenesis of AD – not fully

understood, but several factors have been

implicated in the progression of AD.

DISCUSSION

Among these factors – oxidative stress has been

shown to be involved in AD pathogenesis.

Biomarkers of oxidative damage in DNA are highly

expressed in patients with AD.

Accumulation of DNA damage and the impairment

of its repair mechanism is a prominent feature of

AD.

Although additional studies are required to better

understand the pathogenic mechanisms, especially

the early stages of AD

DISCUSSION

Early administration may be the key to success.

Such agents are relatively safe and highly

available.

Recent biomarker studies indicate that disease

onset commences as much as 10–15 years before

clinical symptoms become manifest.

If simple methods of preclinical diagnosis can be

achieved, a 10-year window may exist for

measures to be instituted that prevent, delay, or

ameliorate the disease.

DISCUSSION

NSAIDs and ibuprofen, provide the best practical

opportunity for therapeutic management of this

principle.

Ibuprofen and related NSAIDs – widely used for the

relatively minor condition of osteoarthritis,

Shown to reduce the risk of AD in multiple

epidemiological studies.

Also – reduce the pathology in even more

numerous transgenic mouse models of AD.

THANK YOU!!!

Alzheimer's disease

Health & Medicine

Transcript of Alzheimer's disease