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Printable Handouts
Navigable Slide Index
- Introduction
- The first AD diagnosis
- Alzheimer's disease
- Alzheimer's disease and Ach (1)
- Alzheimer's disease and Ach (2)
- The goals are straightforward
- AD is a double proteinopathy
- Amyloid beta plaques
- The original 'amyloid cascade' hypothesis
- Protein aggregates in degenerative diseases
- The dogma
- Synapse pathology and fibrils
- A-beta self-assembly takes alternative paths
- Toxic A-beta oligomers (ADDLs) (1)
- Toxic A-beta oligomers (ADDLs) (2)
- Toxic A-beta oligomers (ADDLs) (3)
- ADDLs are potent CNS neurotoxins (1)
- ADDLs are potent CNS neurotoxins (2)
- Clinical relevance of ADDLs
- Toxin specific antibodies
- Human brain extract striking AD-dependence
- Regional specificity
- Structure of ADDLs in AD extracts
- 12mers and memory loss
- The Osaka mutation
- How do oligomers attack neurons?
- Differences between human AD and Tg mice?
- Early ADDLs in human brain
- Pathogenic ligands
- Ligand specificity?
- What is the identity of the targets?
- ADDLs localize to spines
- Extracellular, diffusible… in CSF?
- Alternative for Dx? ADDLs in AD brain tissue
- Targetable magnetic nanostructure
- MRI probes for AD
- Neuropathology of AD
- Insulin receptors
- AD as type III diabetes
- ADDLs and damage to spine structure
- Alzheimer's pathology correlated with dementia
- Binding sites that act as ADDL toxin receptors
- Saturable binding implies receptors
- Fyn receptor
- ADDLs and prion protein
- Role of mGluR5
- Nanoscale artificial membranes (nanodiscs)
- Cell free platform for binding
- Characterizing binding sites in SMPL nanodiscs
- Receptor identification
- Discovery of ADDL binding antagonists (1)
- Discovery of ADDL binding antagonists (2)
- Oligomers' build up in sporadic late onset AD
- Diabetes and AD (1)
- Diabetes and AD (2)
- AD’s synaptic struggle for survival
- Are ADDLs the basis for unifying mechanism?
- ADDL based strategies for Rx
- Acknowledgements
Topics Covered
- The oligomer cascade hypothesis for Alzheimer’s Disease
- why the oligomer hypothesis has largely supplanted the amyloid cascade hypothesis
- the role of AβOs in memory failure and the major facets of AD neuropathology
- mechanisms by which AβOs instigate neurotoxicity
- why AβOs accumulate in the first place
- how AβOs offer superb targets for novel AD diagnostics and disease-modifying therapeutics
- beside its direct link to Alzheimer’s disease, the discovery of toxic Aβ oligomers has provided a novel structural archetype for toxins germane to more than two dozen diseases of protein mis-folding, including diabetes, Parkinson’s, and prion diseases
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Klein, W.L. (2014, February 5). Targeting Aß oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 10, 2024, from https://doi.org/10.69645/UIRL9564.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. William L. Klein has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Targeting Aß oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease
Published on February 5, 2014
68 min
A selection of talks on Cell Biology
Transcript
Please wait while the transcript is being prepared...
0:00
This is Bill Klein at Northwestern University's
Department of Neurobiology
and the NU Cognitive Neurology
and Alzheimer's Disease Center.
I'd like to help you get started
in your investigations of Abeta
oligomers.
This is a truly exciting topic
because it has the potential
for giving us a molecular
basis for the cause, diagnosis,
and treatment of
Alzheimer's disease.
Before we get deep
into Abeta oligomers,
I'd like to take a few minutes
by going to the beginning
and start where we should.
0:33
You might recognize this famous
photo of Auguste D. She was
the first person to
be diagnosed with what
is now called Alzheimer's disease.
Auguste D. came under Alzheimer's
care in 1901 at the age of 51.
At this young age, she was
already showing severe dementia,
including greatly
reduced memory loss.
Within five years, only in her
mid-'50s, Auguste D. was dead.
Alzheimer was an investigator
as well as a clinician,
and he examined Auguste D.'s brain.
He had available to him
new stains and new methods.
And what he discovered
was that Auguste
D.'s brain was riddled with lesions.
Those lesions are illustrated on
the right, and they're of two sorts.
The two figures on the top
illustrate amyloid plaques.
These are extracellular
deposits about the size
of three or four neurons across.
At higher magnification,
as shown on the bottom,
Alzheimer discovered
neurofibrillary tangles.
These are intracellular
deposits, and they
accumulate in diseased neurons.
It is this combination
of dementia, plaques,
and tangles that now
defines the disease.
Alzheimer's is referred to as
dementia with plaques and tangles.
The fact that Auguste D. was so
young set the stage for the belief
that this is a disease
of younger people only.
And it was referred
to for a long time
as presenile dementia
of the Alzheimer's type.
Neurologists used to be taught that
Alzheimer's disease only occurs
in individuals under the age of
65, that it is extremely rare,
and that in most
circumstances, a neurologist
would never find one as a patient.
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