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LDL, Iron, and ApoE4 Interaction: One Possible Root Cause for Alzheimer's
Serenoa
Posted: Saturday, October 28, 2017 5:09 AM
Joined: 4/24/2012
Posts: 483


Inflammation is a critical factor in Alzheimer's disease. An interaction between low density lipoprotein (LDL) cholesterol, iron and ApoE4 at the blood-brain barrier could ignite an inflammatory response in the brain that over time would lead to Alzheimer's pathology. All three of these factors have been independently linked to increased risk of Alzheimer's. Here's one way that their interaction could be the root cause of neurodegeneration. LDL cholesterol in the blood attaches to LDL receptors on cells lining the blood brain barrier. Higher LDL levels create more LDL attachment. These LDL receptors are known to have a greater affinity for ApoE4-carrying LDL over ApoE2 and ApoE3 LDL. And, it has also been shown that LDL receptors don't work as well with ApoE4. So, LDL is not readily taken up by the cell due to the inefficient ApoE4 interaction with the LDL receptor. As cholesterol becomes sequestered for a time on the cell surface, the chances of it being oxidized increase. Iron, especially free iron (Fe2+, Fe3+), is a powerful oxidizing agent which the body tightly regulates, but the body's iron levels are known to increase as we age. Conversely, antioxidants like glutathione are known to decrease as we age. When this LDL cholesterol becomes oxidized by iron at the blood-brain barrier, it triggers an inflammatory response in the brain. Low levels of inflammation in the brain over a long period (chronic inflammation) may be all it takes to induce a cascade of cellular reactions that eventually lead to the well-known pathological features of Alzheimer's like amyloid plaques and tau tangles.

 

Human LDL receptors enhance the sequestration of ApoE4 and VLDL remnants on the surface of hepatocytes but not their internalization in mice

https://www.ncbi.nlm.nih.gov/pubmed/18369154

Iron as a catalyst of human low-density lipoprotein oxidation

http://www.sciencedirect.com/science/article/pii/S0946672X16302826

Body iron stores and early neurologic deterioration 

http://www.neurology.org/content/54/8/1568.short

New research could point the way to halt Alzheimer’s disease: Australian trial set to begin

https://www.florey.edu.au/new-research-could-point-way-halt-alzheimer%E2%80%99s-disease-australian-trial-set-begin

 

 


Lane Simonian
Posted: Wednesday, November 1, 2017 10:50 AM
Joined: 12/12/2011
Posts: 4782


Thanks very much for the useful information and insightful analysis, Serenoa.
Serenoa
Posted: Tuesday, November 7, 2017 5:13 PM
Joined: 4/24/2012
Posts: 483


"Due to the absence of monthly bleeding, iron accumulates in postmenopausal women"

Association of serum ferritin levels with metabolic syndrome and subclinical coronary atherosclerosis in postmenopausal Korean women

http://www.sciencedirect.com/science/article/pii/S0009898114003386


Atherosclerosis is linked to vascular dementia. Iron seems to be a critical player in Alzheimer's. The clinical trial link above is using an iron chelator to remove iron from the brain. 



Serenoa
Posted: Tuesday, November 7, 2017 5:31 PM
Joined: 4/24/2012
Posts: 483


This is a great youtube video. Really helps understand what's going on in the brain. 

Lane please take a look. THis seems to connect vascular damage to excitotoxicity. 

The ischemic cascade in stroke | Circulatory System and Disease

https://www.youtube.com/watch?v=57pvSMQ0E5M 


Lane Simonian
Posted: Wednesday, November 8, 2017 11:23 AM
Joined: 12/12/2011
Posts: 4782


This is one of the most clearly narrated scientific videos that I have ever seen.  This diagram syncs well with the video.

http://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg  (ONOO- is peroxynitrite and GSH is glutathione).

Limiting excitotoxicity and calcium influx and reversing some of the resulting damage to neurons is probably the key to treating Alzheimer's disease.

We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

Several metals including zinc, copper, and iron contribute to oxidative stress in Alzheimer's disease.

Here is one for hydrogen peroxide and peroxynitrite in vascular dysfunction.

https://www.ncbi.nlm.nih.gov/pubmed/10807868