Bace 1 alzheimer s disease
Download
1 / 25

- PowerPoint PPT Presentation


  • 486 Views
  • Uploaded on

BACE 1 & Alzheimer’s Disease By Anisha Vora & Lindsey Wood What is Alzheimer’s? Neurodegenerative disorder characterized by the progressive and irreversible loss of nerve cells (neurons) located in the specific brain areas: the hippocampus and polymodal association areas

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about '' - niveditha


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Bace 1 alzheimer s disease l.jpg

BACE 1 & Alzheimer’s Disease

By Anisha Vora & Lindsey Wood


What is alzheimer s l.jpg
What is Alzheimer’s?

  • Neurodegenerative disorder characterized by the progressive and irreversible loss of nerve cells (neurons) located in the specific brain areas: the hippocampus and polymodal association areas

  • 4th leading cause of death in adults (cases rise with aging)

  • Cortical brain areas heavily filled with two different types of lesions: amyloid plaques and neurofibriallary tangles

    • Amyloid plaques – spherical extracellular amyloid deposits

    • Neurofibrillary tangles – an intra-neuronal accumulation of pathological fibrils called Paired Helical Filaments (PHF) – basis of these tangles is the tau protein


Why this disease l.jpg
Why this disease?

  • Prevalence is increasing

  • United States and Congress has classified the treatment of this disease as a major national priority

  • $100 billion per year is spent on Alzheimer's disease in the United States, making it the third most costly disease after heart disease and cancer

  • 7 million Americans may be afflicted by the year 2010


Plaques tangles l.jpg

Disrupt all three processes

Communication (sending messages)

Metabolism (turning chemicals and nutrients into energy to keep neurons working)

Repair (keeping long-lived neurons in good working order)

Cause nerve cells to stop working, lose connections w/ other cells and eventually die

Destruction causes memory failure, personality changes, etc.

Find abundance of β-amyloid plaques and neurofibrillary tangles, especially in regions for memory

Plaques & Tangles


The changing brain l.jpg
The Changing Brain

  • PET scan measures blood and glucose metabolism giving map of active brain

  • Damage by free radicals increase

  • Shrinking of neurons

  • Increased levels of tangles & plaques develop in AD

Normal Brain

Alzheimer’s Brain


Neurofibrillary tangles l.jpg
Neurofibrillary Tangles

  • Insoluble twisted fibers found inside of brain’s cells

  • Primarily tau, which forms part of structure called a microtubule

  • Microtubule helps transport nutrients and other important substance from one part of nerve cell to another

  • In AD, tau is abnormal and microtubule structures collapse



Amyloid plaques l.jpg
β-Amyloid Plaques

  • Dense, insoluble deposits made of 42 residue β-amyloid peptides

  • Arranged in an anti-parallel arrangement

  • Fragments clump together and are mixed w/ molecules, neurons and non-nerve cells

  • Develop in hippocampus (deep in brain, encode memories) and later in other areas of cerebral cortex (those involved thinking and making decisions)


Amyloid precursor protein l.jpg
Amyloid Precursor Protein

APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell.


From app to amyloid l.jpg
From APP to β-amyloid

Enzymes act on the APP and cut it into fragments of protein, one of which is called beta-amyloid.


From app to amyloid11 l.jpg
From APP to β-amyloid

The beta amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluable plaques.



Bace 1 l.jpg
BACE 1

  • β-Secretase (BACE-1 for β-site APP-cleaving enzyme) is a type 1 transmembrane protein containing aspartyl protease activity

  • 501 amino acids

  • Mediates the primary amyloidogenic cleavage of APP

  • Generates a membrane-bound APP C-terminal fragment-immediate precursor for the intramembraneous γ-secretase cleavage.

  • BACE-1 is the only protease with a well-defined β-secretase activity shown by the homozygous knockout of the BACE-1 gene, which does not allow any Aβ generation

    (Cai et al, 2001; Luo et al, 2001).



3 proteases l.jpg
3 proteases

  • Three proteases, alpha-, ß- and gamma-secretases, are involved in APP processing.

  • At the cell surface, APP undergoes proteolysis by alpha-secretase releasing a large, soluble ectodomain (a-APP; sAPP). The C-terminal fragment is retained within the cell membrane.

  • This fragment can then be cleaved by gamma-secretase releasing the p3 peptide.

  • In an alternate pathway, ß-secretase cleaves APP releasing a large secreted derivative sAPPß and a C-terminal fragment CTFß that can be further cleaved by gamma-secretase to form Aß which is released into the extracellular region.



Structure of bace 1 complexed with inhibitor l.jpg
Structure of BACE 1 complexed with inhibitor

(Hong et al, 2000),

  • Resolution found to 1.9 Angstroms

  • 4 domains

  • Lumenal domain, transmembrane domain, cytosol c-terminal tail

  • Active site is more open and less hydrophobic than other human proteases


Function of bace 1 l.jpg
Function of BACE 1

  • Responsible for the proteolytic processing of the amyloid precursor protein (APP).

  • Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP,

  • Leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.

  • BACE-1 expression is significantly enhanced in brains from patients with AD

  • Reasons for the enhanced expression are currently unclear. Speculated that AD-associated stressors such as oxidative stress, radicals, unfolded proteins, head trauma, and others may induce BACE-1 transcription and/or expression/activity during aging



Drug targeting for ad l.jpg
Drug Targeting for AD

  • BACE-1 is an obvious target for Aβ-lowering drugs.

  • In contrast to γ-secretase, BACE-1 can be fully knocked out in mice without causing any bad phenotypes. Interfering with BACE-1 is unlikely to result in unwanted side effects.

  • The three-dimensional structure of BACE-1 has been solved and peptidomimetic and nonpeptidomimetic inhibitors have already been generated (Hong et al, 2000; Vassar, 2001).

  • Developed further to improve their affinity with the rather large active site cleft of BACE-1 before they can be used in human trials.


Inhibitors of bace 1 invitro l.jpg
Inhibitors of BACE 1 invitro

Table 1.

In vitro values

Cp P3 P1′ X BACE FRET HEK293 Aβ inhibition

at P3’ IC50(uM)a IC50(uM)a

1 CHMe2 Me N 0.082 (±0.023) 2.831 (±0.129)

2 — H H 9.704 (±1.413) >100

3 — Me H 0.285 (±0.016) >100

4 — Me N 4.925 (±0.169) >100

5 — Me H 2.397 (±0.089) >100

6 CHMe2 Me N 0.260(±0.002) 5.305 (±0.191)

7 (S)-MeCHEt(Ile) MeN 0.065 (±0.039) 0.880 (±0.042)

a Values are means of three experiments, standard deviation is given in parentheses.


Bace 1 inhibitors l.jpg
BACE-1 Inhibitors

  • Macrocycles derived from a hydroxyethylene core structure

  • Molecule inhibits production of Aβ peptide in HEK293 cells overexpressing APP751sw

  • Improve potency, Val residue at the P3 position replaced with Ile (compound 7)


Bace 1 inhibitory complex l.jpg
BACE-1 Inhibitory Complex

  • Compound 7 co-crystallized with BACE-1

  • X-ray structure of complex elucidated at 1.6Å resolution to an R-factor of 0.211 using data from the Advanced Photon Source


Future exploration with bace 1 l.jpg
Future Exploration with BACE 1

  • Try to modify inhibitors to have a higher affinity for BACE 1 active site

  • Decrease formation of AB42 and aggregate creation

  • Further cleavage of AB42 to eliminate plaques

  • Breakdown of beta amyloid plaques formed in the brain