Lane, you may be interested in this 2013 paper that discusses amyloid induced oxidative stress...
~~~~~~
Amyloid b-Peptide (1–42)-Induced Oxidative Stress
in Alzheimer Disease: Importance in Disease
Pathogenesis and Progression
Abstract
SIGNIFICANCE:
Alzheimer disease (AD) is an age-related neurodegenerative disease. AD is characterized by progressive cognitive impairment. One of the main histopathological hallmarks of AD brain is the presence of senile plaques (SPs) and another is elevated oxidative stress. The main component of SPs is amyloid beta-peptide (Aβ) that is derived from the proteolytic cleavage of amyloid precursor protein.
RECENT ADVANCES:
Recent studies are consistent with the notion that methionine present at 35 position of Aβ is critical to Aβ-induced oxidative stress and neurotoxicity. Further, we also discuss the signatures of oxidatively modified brain proteins, identified using redox proteomics approaches, during the progression of AD.
CRITICAL ISSUES:
The exact relationships of the specifically oxidatively modified proteins in AD pathogenesis require additional investigation.
FUTURE DIRECTIONS:
Further studies are needed to address whether the therapies directed toward brain oxidative stress and oxidatively modified key brain proteins might help delay or prevent the progression of AD.
~~~~~~~~~
One thing that seems to be common in a lot of what I've been reading lately is that it seems to be amyloid oligomers, more than the downstream larger aggregation into plaques, that are the most toxic form of amyloid in the brain.
And in reading more about tau pathology, a few things I've seen lately discuss the possibility that the precursors to NFTs may be more toxic than the later, larger aggregates.
Several things suggest that it may be a protective measure for the brain to form amyloid plaques and tau tangles... in order to take off the table the more toxic earlier versions of those - not a perfect defense, because those larger aggregates also sequester some important factors, but perhaps better than leaving the earlier versions around... if something has faltered in the upper stream management of amyloid and tau.
I've certainly seen a lot about the toxicity of amyloid and tau, however, whether as early aggregates and/or as later much larger aggregates (plaques and tangles). Even the paper you pointed to yesterday about NFTs being perhaps less toxic than previously thought, had a lot of discussion about the toxicity of Tau hyperphosphorylation.
One paper had the following to say about long-lived neurons that have had a bout with Tau hyperphosphorylation, but have been "saved" from early cell death by some aspects of those same pathologies, including development into the later, perhaps less toxic form of NFTs (as discussed a bit earlier in the same paper):
This comes from the final page of the following 2013 paper:
Abnormal Hyperphosphorylation of Tau:
Sites, Regulation, and Molecular Mechanism
of Neurofibrillary Degeneration
~~~~~
The environment of the diseased brain is enriched
with pro-apoptotic stimuli and the neurons in AD brain
are constantly exposed to the pro-apoptotic factors,
such as oxidative stress and amyloid- [151, 152].
However, there is surprisingly little evidence for the
completion of apoptotic cell death in the AD brain,
implying that a certain mechanism may lead neurons
to escape from apoptosis.
....
...As neurons in adults
are rarely replenished, tau phosphorylation-induced
abortive apoptosis may be one of the evolved mechanisms
which could allow neurons to survive apoptotic
attack and wait for chances of self-repair. [Perhaps
something similar happens with the development
of NFTs, which are perhaps less toxic than
their precursors.]
Although hyperphosphorylation of tau can make
neurons escape from apoptosis and thus prevent
the brain from a rapid loss of many cells, the
neurons with tau hyperphosphorylation are nevertheless
“sick” and no longer competent for normal
physiological functions such as promoting microtubule
assembly and maintaining normal axonal transport.
Additionally, the extended survival time of these “sick”
neurons makes them less resistant to environmental/
metabolic insults and also allows tangles to evolve
from the hyperphosphorylated tau. The hyperphosphorylation
leads to slow but progressive retrograde
degeneration of the neurons...
~~~~~~
I also am learning that there haven't really been satisfactory models that can show both the larger aggregates of (amyloid) plaques and (tau) tangles at work, as would be the case in a human brain, something that Tanzi's model seems to have made important progress with. No doubt, it will at some point be able to include factors that enable the study of oxidative stress on the pathology of AD.
So I want to keep open about what may be found to be related to both of those larger aggregates, to see if they, too, might have some toxic effects.
I certainly will keep an open mind about the things that you're discussing, Lane, as being key. In fact, I'm seeing a lot about oxidative stress in what I'm reading.
But I also definitely don't want to close the door to other perspectives, such as Tanzi's, that would say years of excessive amyloid in the brain (either over produced are not being cleared well enough from the brain) can give rise to tau pathology, which can give rise to inflammation, which can give rise to dementia (a very long road of pathology that apparently includes all sorts of other critical factors along the way, including metals and oxidative stress).
Linda
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