Loading presentation...

Present Remotely

Send the link below via email or IM

Copy

Present to your audience

Start remote presentation

  • Invited audience members will follow you as you navigate and present
  • People invited to a presentation do not need a Prezi account
  • This link expires 10 minutes after you close the presentation
  • A maximum of 30 users can follow your presentation
  • Learn more about this feature in our knowledge base article

Do you really want to delete this prezi?

Neither you, nor the coeditors you shared it with will be able to recover it again.

DeleteCancel

Make your likes visible on Facebook?

Connect your Facebook account to Prezi and let your likes appear on your timeline.
You can change this under Settings & Account at any time.

No, thanks

APP Regulates Brain Lipid Homeostasis

Presentation at the 2013 Society for Neuroscience conference; November 10, 2013.
by

Michael Castello

on 10 November 2013

Comments (0)

Please log in to add your comment.

Report abuse

Transcript of APP Regulates Brain Lipid Homeostasis

APP Regulates Brain Lipid Homeostasis
An adaptive response hypothesis of Alzheimer's disease
Michael A. Castello
1
Most Alzheimer's research is guided by the amyloid hypothesis
amyloid beta is a
symptom
rather than a
cause

2
Alzheimer's research has produced a frustrating lack of effective treatments
AD Characteristics

oligomers
plaques
Tau
hyper-phosphorylation
tangles

oligomers
plaques
Amyloid Hypothesis

X
Some patients have plaques, but
not
AD symptoms
Some patients without plaques
do have
AD symptoms
Commonly explained as
preclinical AD
Commonly explained as
misdiagnosis
However...
These observations are consistent with a model in which Aβ is produced as a
response to stress
STRESS
cholesterol
endocytosis
immune response
Adaptive Response Hypothesis
We would
expect to find
Aβ whenever the brain is under stress
Traumatic brain injury
Ischemia
Synaptic activity
Diabetes
As is the case with other cellular processes, Aβ production can be both
necessary
and
harmful

Cell division
Inflammation
In this model, Alzheimer's disease results from a
prolonged response
to acute and chronic stress that
includes
Aβ production
Cholesterol stress is present in AD
A number of studies have found
altered cholesterol metabolism
in AD brains
Ratio of oxysterols
Lack of decline in cholesterol synthesis
We have observed
cholesterol dysregulation
in
fibroblasts
from AD patients using filipin staining
Control 73 years
AD 73 years
Removing APP increases vulnerability to cholesterol stress...
...and negatively affects cholesterol metabolic pathways
Mouse model of cholesterol dysregulation
instead of
transgenic AD model
NPC1 ko leads to
Aβ production
and
tau hyperphosphorylation
Without APP
symptoms worsen
and
tau is hyperphosphorylated
in the absence of Aβ
Familial AD is a
subset
of AD pathology, rather than an
accelerated model
of the disease
Analysis via
Transcriptome-to-Metabolome™
(TTM) biosimulation in collaboration with Dr. Clyde Phelix
A technique that has been
validated
in
human AD
[4] Phelix et al, 2011
APP knockout
alone
has a
detrimental effect
on cholesterol metabolism
Possibly a true
preclinical

AD
These changes occur due to
APP knockout alone
Where does this leave us?
Amyloid Hypothesis
The amyloid hypothesis has
outlived its usefulness
and is
no longer supported
by the data
An adaptive response hypothesis is better
supported by data
, is
testable
, and offers
new possibilities
for research and treatment of AD
Adaptive Response Hypothesis
It's time to evolve.
Acknowledgments
Dr. Salvador Soriano
Dr. Ana Nunes
Dr. Clyde Phelix

Kristy Howard
Funding by Alzheimer's Research Trust, UK; Medical Research Council, UK; Loma Linda University Department of Anatomy
Soriano Neurodegenerative Diseases Laboratory
Loma Linda University
Two observations about Alzheimer's disease (AD) research:
[1] Hollingworth et al, 2011
[2] Castello and Soriano, 2013
[3] Nunes et al, 2011
Michael A. Castello
Presentation CC-BY-SA 2013 Michael A. Castello Literature references follow and are also available upon request. Branding by Caitlyn Mayers Design. This has been a modulate-free presentation.
castello.me
References
1. Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).

2. Castello, M. A. & Soriano, S. Rational heterodoxy: Cholesterol reformation of the amyloid doctrine. Ageing Res. Rev. 12, 282–288 (2013).

3. Nunes, A., Pressey, S. N. R., Cooper, J. D. & Soriano, S. Loss of amyloid precursor protein in a mouse model of Niemann-Pick type C disease exacerbates its phenotype and disrupts tau homeostasis. Neurobiol. Dis. 42, 349–359 (2011).

4. Phelix, C. F. et al. Transcriptome-To-Metabolome Biosimulation Reveals Human Hippocampal Hypometabolism with Age and Alzheimer’s Disease. Int. J. Knowl. Discov. Bioinforma. 2, (2011).

Full transcript