Case of mistaken identity: Study questions role of A-beta molecules in Alzheimer's disease pathology
June 28, 2011 in Neuroscience
Confocal microscope image of neurons in the 3xTgAD mice stained for the amyloid-ß (Aß) precursor protein (APP) showing APP (green) within these nerve cells which were not labeled by antibodies that detect free Aß, the peptide cleavage product of APP that, when released from APP by proteases will be secreted and for Alzheimer plaques outside nerved cells in the brain of these mice similar to Alzheimer patients. Credit: Edward B. Lee, Perelman School of Medicine at the University of Pennsylvania
Increasingly, researchers are suggesting that amyloid plaques and neurofibrillary tangles may be relatively late manifestations in the course of Alzheimer's disease (AD) pathology. Identifying earlier events in the development of AD remains a challenge. The laboratory of Virginia M.-Y. Lee, PhD, director of the Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, was the first, in 1993, to demonstrate unequivocally the presence of A-beta peptides -- a hallmark of AD -- inside neurons. But their role in Alzheimer's disease remained unclear.
"It was exciting when a 'triple transgenic' mouse model of AD was reported in 2003 to show robust staining of cells interpreted as A-beta peptides inside neurons," says Edward Lee, MD, PhD, assistant professor of Pathology and Laboratory Medicine, co-author on a study just out in the Journal of Neuroscience that questions the role of A-beta peptides in AD pathology.
The triple transgenic mouse has since become a popular model in AD studies, says Edward Lee. In these mice, A-beta molecules were detected before amyloid-plaque and neurofibrillary-tangle pathology showed up, suggesting that intraneuronal A-beta peptides lead to amyloid plaques, which then lead to neurofibrillary tangles inside neurons.
The Penn researchers examined the trajectory of neuronal inclusions over time using rigorous biochemical and genetic methods. Virginia Lee's group discovered a case of mistaken identity: The intraneuronal molecules appear not to be A-beta peptides themselves, but rather the A-beta amino acid sequence nested within its parent protein, the A-beta precursor protein. What's more, blocking A-beta peptides from forming in the triple transgenic mice had no effect on the formation of neurofibrillary tangles.
According to Virginia Lee, this finding is significant for Alzheimer drug development because it underlines the need for tau-focused drug discovery for AD since the idea that intracellular A-beta drives tangle formation was not substantiated. Therapies aimed at blocking A-beta production may not have any effect on tangle formation, which is consistent with human clinical trial data to date.
The role of intraneuronal A-beta in AD is still unclear, but these results have profound implications for studies of mechanisms of AD and for AD drug discovery since mouse models of presumptive intracellular A-beta are widely used, state the authors.
Please take a look at the Alzforum webinar about the debate on intraneuronal A-beta as a potential instigator of Alzheimer's disease: http://www.alzforu … p?liveID=193
More information: Paper: http://www.jneuros … 691.abstract
Provided by
University of Pennsylvania School of Medicine
-
Compounds fend off Alzheimer's disease amyloid pathology
Sep 08, 2010 |
not rated yet |
0
-
Novel mouse gene reduces major pathologies associated with Alzheimer's disease
Nov 11, 2009 |
not rated yet |
0
-
Common epilepsy drug could prevent and treat Alzheimer's disease
Oct 27, 2008 |
not rated yet |
0
-
Asthma drug could help control or treat Alzheimer's disease
Mar 25, 2011 |
not rated yet |
0
-
Mechanism explains link between apolipoprotein E and Alzheimer's disease
Jun 11, 2008 |
not rated yet |
0
-
Limits to growth: Scientists identify key metastasis-enabling enzyme
May 22, 2012 |
5 / 5 (3) |
0
-
Seeing is as seeing does: Spatially-structured retinal input in early development of cortical maps
Apr 26, 2012 |
5 / 5 (4) |
1
-
Dreamless nights: Brain activity during nonrapid eye movement sleep
Apr 09, 2012 |
4.4 / 5 (12) |
0
-
Take your time: Neurobiology sheds light on the superiority of spaced vs. massed learning
Mar 28, 2012 |
4.5 / 5 (21) |
3
-
Your brain on 'shrooms: fMRI elucidates neural correlates of psilocybin psychedelic state
Feb 29, 2012 |
4.9 / 5 (42) |
45
-
A question about drug tolerance
21 hours ago
-
Poor nutrition leading to overeating?
May 23, 2012
-
Math and dyslexia?
May 21, 2012
-
portable metabolism meter?
May 21, 2012
-
Rare medical conditions on 20/20 tonight
May 18, 2012
-
"Good" Cholesterol in Doubt
May 17, 2012
- More from Physics Forums - Medical Sciences
More news stories
Persistent sensory experience is good for aging brain
Despite a long-held scientific belief that much of the wiring of the brain is fixed by the time of adolescence, a new study shows that changes in sensory experience can cause massive rewiring of the brain, even as one ages. ...
Neuroscience
4 hours ago |
not rated yet |
0
Boundary stops molecule right where it needs to be
A molecule responsible for the proper formation of a key portion of the nervous system finds its way to the proper place not because it is actively recruited, but instead because it can't go anywhere else.
Neuroscience
4 hours ago |
not rated yet |
0
|
Locating ground zero: How the brain's emergency workers find the disaster area
Like emergency workers rushing to a disaster scene, cells called microglia speed to places where the brain has been injured, to contain the damage by 'eating up' any cellular debris and dead or dying neurons. ...
Neuroscience
4 hours ago |
5 / 5 (2) |
0
|
Genetic 'reset switch' enables signaling pathway to induce multiple developmental outcomes for olfactory neurons
Within the nervous system, a handful of signaling pathways modulate development of a cornucopia of different neuronal subtypes. “Even small alterations in neuron differentiation pathways can disrupt subsequent ...
Neuroscience
7 hours ago |
not rated yet |
0
The auditory cortex adapts agilely with concentration
The birth of sensory perception on the human cerebral cortex is yet to be fully explained. The different areas on the cortex function in cooperation, and no perception is the outcome of only one area working alone. In his ...
Neuroscience
8 hours ago |
not rated yet |
0
Amino acid consumption associated with how fast cancer cells divide
For almost a century, researchers have known that cancer cells have peculiar appetites, devouring glucose in ways that normal cells do not. But glucose uptake may tell only part of cancer's metabolic story. Researchers from ...
Cyber exercise partners help you go the distance: Motivation gains can double
A new study testing the benefits of a virtual exercise partner shows the presence of a moderately more capable cycling partner can significantly boost the motivation – by as much as 100 percent – ...
Childhood cancer scars survivors later in life
Scars left behind by childhood cancer treatments are more than skin-deep. The increased risk of disfigurement and persistent hair loss caused by childhood cancer and treatment are associated with emotional distress and reduced ...
Report: State tobacco prevention funding lacking
(AP) -- States have spent only about 3 percent of the billions they've received in tobacco taxes and legal settlements over the last decade to fund tobacco prevention programs, making it harder to reduce the death and disease ...
Low vitamin D in diet increases stroke risk in Japanese-Americans
Japanese-American men who did not eat foods rich in vitamin D had a higher risk of stroke later in life, according to results of a 34-year study reported in Stroke, an American Heart Association journal.
Doctors group warns EU health care access shrinking
Access to health care is declining in Europe, and Greece in particular faces a humanitarian crisis as it cuts health and social spending, aid group Doctors of the World warned Thursday.
