Alzheimer's disease

Alzheimer’s Disease

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• What’s Alzheimer’s Disease(AD)?• Signs/Symptoms• Stage of progression• Risk factors• Pathology• Ethiology

– Beta-amyloid– Tau

Outline

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What’s Alzheimer’s Disease(AD)?

• AD is an illness of the brain. It causes large numbers of nerve cells in the brain to die.

• AD is a progressive, irreversible brain disease that destroys memory and thinking skills.

• Most common cause of dementia in adults

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Pathology

• Amyloid plaques,• Neurofibrillary tangles• Neuron and Synapse loss• Neuronal cell death

Amyloid plaque

NFTs

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Sign and Symptom• Memory loss• Difficulty performing familiar tasks• Problems with language• Disorientation to time and place• Poor or decreased judgment• Problems with abstract thinking• Misplacing things• Changes in mood or behavior• Changes in personality• Loss of initiative

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Stage of progression

• Stage 1 (Mild)– 2 to 4 years – Less energetic and spontaneousEx. of behaviors– Getting lost– Repetitive questions and conversations– Losing things or misplacing them in odd places– Noticeable changes in personality or mood

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Stage of progression (Con.)

• Stage 2 (Moderate):– 2 to 10 years– Clearly disable– Forget recent events and their personal history– More disoriented and disconnected from reality– Speech problems arise and understanding– Reading and writing are more difficult

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• Stage 3 (Severe): – 1 to 3 years during final stage– lose the ability to feed themselves, speak,

recognize people and control bodily functions– Their memory worsens and may become almost

non-existent. They will sleep often and grunting or moaning can be common.

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Risk factors

• Age– After age 65, and rises sharply after age 75

• Genetics– Family history of AD

• Sex– Women > Men

• Having Down syndrome

Cell damage

Cerebral cortex

Hippocampus Long-term memory/Short-term memory

Neurotransmitter deficits: NE: depression

5-HT3: Depression/Anxiety

ACh: Memory and Cognition loss http://www.memorylossonline.com/glossary/hippocampus.html

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β-amyloid (Aβ)

• Aβ peptides 36-43 amino acids• Prevalence of Aβ peptides : Aβ40, Aβ42

• Amyloid hypothesis : Aβ monomer Soluble oligomers (2-6 peptides) Amyloid plaques (insoluble fibers) Alzheimer’s disease

1. Imbalance between production and clearance2. Aggregation of peptides Accumulation of Aβ

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β-amyloid production

APP : amyloid precursor protein (type-1 transmembrane glycoprotein)BACE-1 : beta-site amyloid precursor protein-cleaving enzyme 1 β-SecretasesAPP : large amyloid precursor proteinC83, C99 : 83, 99-residue carboxyl-terminal fragmentAICD : amyloid intracellular domain

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Aggregation & accumulation of Aβ Aβ monomer

Soluble oligomers • Aβ40 > Aβ42, 2-6 peptides

• The most neurotoxic : dimers & trimers toxic to synapses

Amyloid plaques or insoluble fibers in neocortex (Neocortex sensory perception, generation of motor

commands, spatial reasoning, and language)

Pathological features of Alzheimer’s disease (as well as NFT in medial temporal-lobe)

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Pathological features of Alzheimer’s disease

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Clinical trials of therapeutic management

• ɣ-secretase inhibitor (LY450139)• Vaccination

– Phase 2a trial (NCT00021723) : encephalitis and no cognitive

– Phase 2 trial (passive immunization of NCT00112073) : vasogenic cerebral edema in some patients

– Phase 3 trial (NCT00574132 & NCT0088662)

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Vaccination

Dale Schenk, Michael Hagen, Peter Seubert. Current progress in beta-amyloid immunotherapy. Current Opinion in Immunology, Volume 16, Issue 5, October 2004, Pages 599-606

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• Proteases neprilysin : a membrane-anchored zinc endopeptidase Degradation of Aβ monomers & oligomers

• Insulin-degrading enzyme : a thiol metalloendopeptidase Degradation of monomer

• Overexpression Prevent plaque formation

[ Tau & Neurofibrillary tangles ]

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Axonal transport

http://www.mpih-frankfurt.mpg.de/global/Nc/view.htmhttp://www.colorado.edu/intphys/Class/IPHY3430-200/002cellular.htm

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Structural organization of microtubule

http://manual.blueprint.org/Home/glossary-of-terms/mechano-glossary--m/mechano-glossary-microtubules

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Tau protein• Stabilization and assembly

of microtubule

• Vesicles transport

• Phosphorylation dependent

• Phosphotau and total Tau in CSF as predicting markers

http://www.gate2biotech.com/early-testing-for-alzheimers-disease/

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What accelerate Tau accumulation ?

• Oxidative stress

• Impaired protein-folding function

• Deficient proteasome-mediated proteins clearance

24http://missinglink.ucsf.edu/lm/ids_104_neurodegenerative/Case1/Case1Micro2.htm

Neurofibrillary tangles

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Approaches for therapeutic agents

• Inhibitors of Tau oxidation and aggregationMethylene blue, NCT00568776“Under way”

• Polyphenolic agentGrape seeds extracts: Resveratrol Aging-suppressor gene

The Synapse in The Synapse in Alzheimer’s DiseaseAlzheimer’s Disease

• Alzheimer’s disease is primarily disorder of synaptic failure.

• Synaptic failure– decrease in number– functional deficit

Synaptic failureSynaptic failure

Depletion of Neurotrophin

Neurotrophins are a family of proteins that induce the survival, development and function of neurons.

learning memory behavior

Neurotrophin

Types of Neurotrophin

1. Nerve growth factor (NGF)

2. Brain-derived neurotrophic factor (BDNF)

3. Novel Neurotrophin-1 (NNT-1)

4. Neurotrophin-3 (NT-3)

5. Neurotrophin-4 (NT-4)

Depletion of neurotrophin

Depletion of neurotransmitterDepletion of neurotransmitter

“Cholinergic hypothesis” Loss of cholinergic function in the CNS contributes significantly

to the cognitive decline associated with advanced age and AD

Building up of - Amyloid and tua

Deficiency of cholinergic projection

Alzheimer’s disease


Evident • ↓Presynaptic α7-nicotinic Ach receptor (nACh-R)¥ Aβ bind to α7-nACh-R impair its signaling and the

release of Ach.• ↓Muscarinic ACh receptor¥ Stimulate postsynaptic M1 ACh-R

→ activate PKC favoring processing of amyloid precursor protein that does not yield amyloid.

Activation of nACh-R or M1-R limited tau phosphorylation


• Cholinesterase inhibitor improve neurotransmission but it loss efficacy over time.

• M1 agonist showed improvement in cognition and reduced Aβ levels in the cerebrospinal fluid.

(but this agent are toxic)

Synaptic Dysfunction in Alzheimer’s DiseaseSynaptic Dysfunction in Alzheimer’s Disease

Mitochondrial Dysfunction in Alzheimer’s Disease

Mitochondrial Dysfunction• -amyloid (A) is potent

mitochondrial poison• A inhibits key mt. enzyme

esp. Cyt. c oxidase• Impairment of electron

transport, ATP production, oxygen consumption and mt. membrane potential

• Increase in mt. superoxide (O2-)

radical formation H2O2 oxidative stress, cyt. C release and apoptosis

Cyt. C oxidase

http://pharmrev.aspetjournals.org/content/54/1/101/F1.large.jpg

Mitochondrial Dysfunction• ROS & RON interact with

lipid mb, mb proteins• Lead to mitochondrial

mb potential (MMP) collapses

• Lead to opening of mitochondrial permea-bility transition pore (form when mitochodrial get damaged) apoptosis

• Antihistamine agent dimebolin improve cognition and behavior in patients with mild to modest

• Act on NMDA & mt. pore

New England Journal of Medicine. 362(4):329-344, January 28, 2010.

Promote tau phosphorylation

TCA cycle

Accumulation of mtDNA mutation

Stress-activated p38 and JNK

Toxic aldehyde disturbs glu transportation

Mitochondrial Dysfunction Oxidative Stress

• Dysfunctional mt. release oxidizing free radicals oxidative stress

• Experimental model show oxidative damage markers occur prior to pathological changes

• A generator of ROS and NOS oxidative stress• RAGE (receptor for advanced glycation end products)

mediate A ’s pro-oxidant effects on neuron, microglial & cerebrovacular cells


Amany Mohamed , et. al., Int J Alzheimers Dis. 2011, 127984.

A can be translocated to the cellvia interacting with RAGE


A can be translocated to mt via TOM

Inhibit cyt. c oxidase lead to ROS and oxidative stress

Renato X. Santos, et. al., -Int J Clin Exp Pathol 2010;3(5):570 581


• Elevated levels of free divalent transition metal (Fe, Cu and Zn) and Aluminum related with ROS damage and neurodegeneration

• Seek for therapeutic approach to deal with divalent metals• So far, safe compound derived from clioquinol (PBT2) – show

some efficacy


http://clinicaltrials.gov/

Mitochondrial Dysfunction Insulin Signaling Pathway

• Observation of subgroups of AD advanced AD have high fasting insulin levels & low rates of glucose

disposalLevels of insulin receptors, GLU-transport proteins and other

insulin-pathway components in brain are reduced in some studies with AD

• Resistance to insulin signaling energy deficiency in neuron and prone to oxidizing or other metabolic insults and impairs synaptic plasticity

• High serum glucose --> up regulate the tau kinase, glycogen synthase kinase 3 and reduce levels of insulin-degrading enzyme in the AD’s brains

• Thiazolidine (PPAR agonist) activate insulin responsive gene transcription had significant effects in some AD patients

Mitochondrial Dysfunction Insulin Signaling Pathway

• It is not clear whether signaling is up-regulated (compensatory) or down-regulated (pathologic) in AD

Douglas C.Wallace, et. al., -Annu. Rev. Pathol. Mech. Dis. 2010.5:297 348.

ALZYMER’S DISEASE

DEFINING PHATOLOGICAL AND BIOCHEMICAL CARACTERISTICS

• Amyloids plaques(extracellular)• Neurofibrillary tangles(intracellular)• Inflammation(astrocytosis, miccrogriosis,

cytokines, complement, acute phase inflammatory proteins)

• Selective neuronal degeneration• Synaptic loss• Multiple neurotransmitter deficits

VASCULAR EFFECTS IN ALZHEIMER’S DISEASE

VASCULAR EFFECT OF ALZHEIMER’ S DISEASE

• Vascular dementia• Cerebral amyloid angiopathy• Capillary abnormalities• Disruption of blood brain barrier• Large-vessel atheroma

None of these changes alone explain the symmetric reductions of cerebral blood flow in patients with Alzheimer's disease

Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ruitenberg A, Ann Neurol. 2005

• Cerebral blood flow (CBF) velocity is decreased in patients with Alzheimer's disease.

• It is being debated whether this reflects decrease because of advanced neurodegeneration or cerebral hypoperfusion contributes to dementia

• Although they cannot prove that this is caused by preclinical neurodegeneration leading to hypoperfusion

• But they suggest that cerebral hypoperfusion precedes and possibly contributes to onset of clinical dementia

Atherosclerosis of Cerebral Arteries in Alzheimer Disease Alex E. Roher, MD PhD; Stroke. 2004

Large-vessel atheroma• Vascular disease underlies Alzheimer dementia• Atherosclerotic lesions and large leptomeningeal

vessels were found to correlate with Alzheimer disease (AD) clinical diagnosis and neuropathology

• AD pathology is the complex end result of slowly evolving vascular disease and parenchymal lesions

Inflammation and Mechanism of Aβ Clearance

VASCULAR CHANGED IN ALZHEIMER’S THERAPY

Immunotherapy

Angiotensin-converting-enzyme inhibitor

Folic acid

Advance glycation end product inhibitor

The reduction of cognitive decline

Reduced homocyteine level and may lower the risk of AD but not improve cognitive

Phase 2 study in mild-to-Moderate AD

Might be concern increasedvascular amyloid, microhemorrhages, vasogenicedema

Chronic microglia activation and macrophage infiltration in Alzheimer’s disease

http://www.nature.com/nrn/journal/v6/n9/fig_tab/nrn1725_F2.html

Inflammatory-activated glia co-cultured neurons

http://www.neuroscience.cam.ac.uk/directory/profile.php?gcb3

Some components of the inflammatory to CNS degeneration

http://www.gladstone.ucsf.edu/wp/2009/10/inflammationalzheimers/

Inflammatory responses and neurodegeneration


Neurotoxic and neurotrophic action of microglia and astrocytes

McNally L, Bhagwager Z, Hannestad J, CNS Spectr, Vol 13 NO.6. 2008.

Using the inflammatory response against AD


INFLAMMATION IN ALZHEIMER’S THERAPY

Aβ Immunization, TNF-α andComplement factor blocker agents

Nonsteroidal anti-Inflammatory agent

Lower the risk’s of AD and slow progression of disease themechanisms of action is selectivereduction of Aβ 42, Inhibition of COX 2 or prostaglandin receptor,stimulation of phagocytosis by microglia (Only in prospectiveObservation study)

Not show evidence of reducingThe risk of AD or slowing cognitive decline

Nonsteroidal anti-Inflammatory agent and derivative(Tarenflubil)

Being investigated

Calcium

Presenilin

mutation

Disrupt calcium homeos

tasis Aβ level

Calcium in endoplasmic

reticulum

Release calcium

into cytoplas

m


Calcium In late stage of


Glutaminergic

receptor activation

+

Cytosolic calcium

Calcium – release channel

in ER

Axonal – transport deficit

• Kinesin family drive vesicles and mitochondia destined for the synaptic terminal along axonal microtubules.

• BACE 1 ( amyloid precursor protien) and presenilin 1 were reported to undergo fast anterograde transport into terminal fields where Aβ and proteolytic derivatives are released

Axonal – transport deficit

Impairment of transport

Amyloid precursor protein, vesicle and kinesin

Exonal swelling, Aβ deposition and neurodegeneration

Aberrant Cell-Cycle Reentry

http://www.nature.com/nrn/journal/v8/n6/box/nrn2097_BX2.html

Oxidative stress DNA-damaging agents

Cholesterol Metabolism

http://en.wikibooks.org/wiki/File:Lipid_Raft*.png


http://www.rndsystems.com/cb_detail_objectname_WI00_BaceAlzheimers.aspx

promoted and clearance from the brain is reduced

promoted and clearance from the brain is reduced


http://www.gladstone.ucsf.edu/wp/2009/10/alzheimersandapoe/


High serum cholesterol levels


Statins-reduce the membrane pool of free cholesterol-reductions in inflammation- up-regulation of α-secretase and vascular function

Definition

• Advanced glycation end products (AGEs) are formed as a result of nonenzymatic reactions between intracellular glucose-derived dicarbonyl precursors (glyoxal, methylglyoxal, and 3deoxyglucosone) with the amino groups of both intracellular and extracellular proteins

Effective treatment for sporadic Alzheimer’s disease rests on

• Translation of the disease pathways

• Additional molecular mechanisms or new risk genes (eg. Apolipoprotein J)

Eg, of recently discovered proteins encoded by these risk genes include -

• Apoliprotein J(clusterin)

• TOMM 40

• Sortillin-related receptor

levels are reduced in the brain of patients with AD and mild cognitive impairment

Another potential risk factor for sporadic AD• (General anesthesia) promote-

• tau insolubility• A β oligomerization• Deficiency of estrogen in brains of post-menopausal women• Chronic activation of the glucocorticoid axis

• Normally tau protein is soluble and abundant in axons

• Hyperphosphorylated tau is insoluble and lacks affinity for microtubules and self-associates into paired helical structures

• It’s already observed that the correlation between the levels of A β oligomers in the brain and severity of cognitive defect in AD

• Oligomers and protofibrils are considered potent blockers of long-term potentiation that involved in memory formation

• But does these factors lead to amyloid deposition and tauopathy in human is still in question?

• Recent studies point to brain atrophy and other pathologic conditions, not severe amyloid or tangle load, in accounting for dementia in the oldest ones

• Prospective studies show that cognitive leisure activity and training can lower the risk of demensia

• Possible that many of these mechanisms (including the amyloid hypothesis) are minor or wrong and some critical aging-related process is the disease trigger

Alzheimer's disease

Health & Medicine

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