Alzheimers disease

Woro Harjaningsih

References :
Mc Phee, S. J and Hammer, G. D,2010 Pathophysiology of disease :An Introduction to Clinical Medicine, 6 th Ed, Mc Graw Hill Lange Mc Phee, S. J, Lingappa, V. R, Ganong, W. F, and Lange, J. L, 2000, Pathophysiology of Disease, 3 rd Ed, Lange

I know begin the journey that will lead me into the sunset of my lifeRonald Reagan

In 1906 Dr Alois Alzheimer noticed changes in the brain tissues of a woman who had died of an unusual mental illness. He found abnormal clumps (now called amyloid plaques)and tangled bundles of fibers (now called neurofibrillary tangles). Today, these plaques and tangles in the brain are considered hallmarks of AD.

Case
A 73 years old woman prepares a chicken for dinner. Family members discover hours later that she had placed it in the washing machine to bake. A 69 year-old woman does not recognize her husband when he returns from the grocery store. She accuses him of stealing her car and calls the police.

Takrif : suatu sindrom demensia yang ditandai dengan penurunan ingatan dan kemampuan kognitif pasien secara progresif.

Etiologi
Belum diketahui secara pasti Kemungkinan ada faktor genetik (ApoE atau secretase) dan lingkungan Faktor risiko Usia Riwayat keluarga Abnormalitas pada gen Apolipoprotein E (ApoE) terutama pada ras Kaukasian

Alzheimer's biasanya didiagnosis dari riwayat pasien, observasi klinik dan gambaran neurologi dan neuropsikologi Pemeriksaan lanjut dengan computed tomography (CT) atau magnetic resonance imaging (MRI), dan dengan single photon emission computer tomography (SPECT) atau positron emission tomography (PET)

PET scan of the brain of a person with AD showing a loss of function in the temporal lobe.

Patogenesis
Secara anatomi, ada 4 perubahan mayor dalam struktur otak : a. Atrofi kortikal b. Degenerasi kolinergik dan saraf lain c. Adanya neurofibrillary tangles d. Akumulasi plak neuritik

Patogenesis
Pasien umumnya mengalami atrofi kortikal dan

berkurangnya neuron secara signifikan terutama syaraf kolinergik Kerusakan saraf kolinergik terutama pada daerah limbik otak (terlibat dalam emosi) dan korteks (terlibat dalam memori dan pusat pikiran/advanced reasoning center) Terjadi penurunan jumlah enzim kolin asetiltransferase di korteks serebral dan hippocampus penurunan sintesis asetilkolin di otak

 Di otak juga dijumpai lesi yang disebut senile (amyloid)

plaques dan neurofibrillary tangles, yang terpusat pada daerah yang sama dimana terjadi defisit kolinergikplak tersebut berisi deposit protein yang disebut amyloid Amyloid = istilah umum untuk fragmen protein yang diproduksi tubuh secara normal Beta amyloid = fragmen protein yang terpotong dari suatu protein yang disebut Amyloid Precursor Protein (APP) yang dikatalisis oleh secretase Pada otak orang sehat, fragmen protein ini akan terdegradasi dan tereliminasi

 amyloid sendiri juga dijumpai pada geriatri yang

normal tetapi tidak terkonsentrasi pada korteks dan sistem limbik Pada pasien Alzheimers , fragmen ini terakumulasi membentuk plak yang keras dan tidak larut amyloid membentuk plak karena berikatan dengan suatu protein yang disebut Apolipoprotein E4(ApoE4)menjadi insolublekarena itu ApoE4 terlibat dalam patofisiologi Alzheimers disease

 Neurofibrillary tangles ? Terdiri dari dua serabut terpilin yang tidak larut yang

terdapat pada sel-sel otak Serabut2 ini terutama terdiri dari protein yang disebut tau, yang membentuk bagian dari suatu microtubulus Pada penderita Alzheimers,protein tau ini menjadi tidak normal, tidak dapat mengikat microtubulus dan menyebabkan struktur microtubulus menjadi rusak Microtubule ? berfungsi membantu transport nutrien dan substansi penting lainnya dari satu bagian sel saraf ke bagian lainnya

Two Major Hypotheses for AD:

protein or APP (the amyloid beta 42 residue fragment or Ab-42) leads to the formation of plaques that someone kill neurons.
2. TAUists: Abnormal phosphorylation of tau proteins makes them

sticky, leading to the break up of microtubules. The resulting loss of axonal transport causes cell death.

(Recently a presenilin hypothesis has been proposed by Shen & Kelleher (2007), PNAS, 104:403-408.)

Amyloid Hypothesis
(its the plaques, dummy)
1. The amyloid precursor protein (APP) is broken down by a series of secretases (see next two slides).
2. During this process, a nonsoluble fragment of the APP protein (called Ab42) accumulates and is deposited outside the cell. 3. The nonsoluble or sticky nature of Ab-42 helps other protein fragments (including apoE) to gather into plaques. 4. Somehow the plaques (or possible the migration of Ab-42 outside the cell) cause neuronal death. 5. PSEN1 & PSEN2 genes subunits of g secretase.

Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends outward. It is though to be important for neuronal growth, survival, and repair.

From: www.niapublications.org/pubs/unraveling/01.htm

Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or Ab. From: www.niapublications.org/pubs/unraveling/01.htm

Beta-amyloid is sticky so the fragments cling together along with other material outside of the cell, forming the plaques seen in the AD brain. From: www.niapublications.org/pubs/unraveling/01.htm

b-secretase Pathway: (not drawn to scale) APP Protein:

g g

(1) b-secretase cuts APP protein, giving:

(2) g-secretase cuts this residue, giving:

or

Tau Hypothesis
(its the tangles, dummy)
1. Ordinarily, the t (tau) protein is a microtubule-associated protein that acts as a three-dimensional railroad tie for the microtubule. The microtubule is responsible for axonal transport.
2. Accumulation of phosphate on the tau proteins cause paired helical filaments or PHFs (like two ropes twisted around each other) that accumulate and lead to the neurofibrillary tangles (NFT). PHFs are the main component in NFTs/neurofibrillary tangles 3. Impaired axonal transport is the probable cause of cell death. 4. Focus on MAPT gene (microtubule-associated protein tau) 5. Not in favor anymore.

Current theory: Multifactorial, involving several pathways.

Protein accumulation: placques & tangles Inflammation: Unregulated activation of glia Lipid distribution: Lipid membrane site of APP cleavage.

From Sleegers et al. (2010) Trends in Genetics, 26, 84-94, p. 87

Alzheimers Disease

http://www.ambion.com/tools/pathway/pathway.php?pathway=Alzheimer's%20Disease%20Pathway

Current gene candidates for AD:

Changes too rapidly to keep track of. Go to http://Alzgene.org for latest list

Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as ties that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing the structure of the microtubule. Loss of axonal transport results in cell death.

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