Though neuronal cell death is the pathologic end-point in Alzheimer's disease (AD), intense research efforts have not clarified the primary mechanisms or metabolic defect that results in neuronal cell death.
In particular, previous works have not answered the question, is AD a vascular or metabolic disorder?
Although vascular pathology has been described in AD, relatively little is known about the pathogenic mechanisms by which brain endothelial cells and vascular pericytes contribute to dementia and lesions in AD brains.
According to the current concept, the brain vascular system is continually modified in order to maintain adequate cerebral blood flow and brain perfusion.
But vascular growth and repair mechanisms during normal aging and neurodegenerative disorders such as stroke and vascular dementia are still poorly understood.
The lesions such as senile plaques and neurodegenerative changes could have a primary cause from dysfunctional endothelium.
The cerebro-microvasculature might be a key player in the pathogenesis of AD.
Evidence has been presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.
Furthermore, the primary role of endothelial cell pathology in amyloid plaque deposition has given some substance to the importance of vascular pathology as a primary agent in AD.
The vascular pathology may be related to an inflammatory response such as appears to be the case in atherosclerosis, or alternatively a yet-to-be defined inflammatory response of the brain may lead to angiopathy.
Whereas other investigators have espoused the systemic nature of AD, what has not appeared in the discussion of the role of the vascular system in dementia is the hypothesis that some dementias may be the result of defects in the progenitor endothelial cells of patients who eventually manifest neurodegeneration as a consequence of the resultant angiopathology.
Vascular endothelial cells form a single cell internal lining of the lumen of all the blood vessels in the body.
The endothelium is the multifunctional interface between the blood and tissues.
By means of molecular signals expressed on the surface or molecules released from the surface to the blood, the endothelial cell can change from a smooth passive surface to a sticky surface, which attracts molecules and cells such as granulocytes, monocytes, lymphocytes and platelets.
While it is clear that endothelial cells secrete a wide variety of chemotactic molecules as well as cytokines, its reproductive and regenerative capabilities have received little attention.
In the past, repair or regeneration of the endothelial cell lining of blood vessels had been believed to be through local migration and proliferation of cells adjacent to the site of injury; however, the presence of endothelial progenitor cells in the circulating blood was also described.
These cells are known to incorporate into endothelium and repair defects.
The evidence for the importance of endothelial progenitor cells comes also from the observation of chimerism in renal and liver transplantation over 20 years ago wherein cells of the host were found to invade the graft as a response to endothelial injury.
A more recent demonstration of the important role of bone marrow-derived progenitor cells is the successful neovascularization in the myocardium by these cells.
The endothelium is also a critical regulator of vascular volume or tone through the production and release of nitric oxide, leading to the relaxation of smooth-muscle cells in the vessel wall.
In addition the cell in capillaries may swell and shrink in response to stimuli (Figure 1).
Recently one of the tremendously important roles of the endothelial cell has been recognized as being closely related to insulin resistance, diabetes, hypertension, inflammation and atherosclerosis, but little attention has been paid to the capabilities of the endothelial cell to repair and remodel vessels or to the origin of endothelial cells.
Models of human cerebral capillary networks and proposed mechanisms of capillary filling.
A: The concept of a through-channel normal flow with recruitment of unfilled capillaries (generally no longer accepted).
B: The general model from skeletal muscle studies showing control of capillary bed filling from arteriolar smooth muscle sphincters.
C: A new concept to explain capillary filling through endothelial cell shrinkage which occurs in addition to arteriolar control of blood flow into the capillaries.
D: An alternate mechanism to C (above) to explain capillary network volume changes through the action of pericytes
Endothelium and Alzheimer's Disease
The connection between the endothelium and Alzheimer's disease comes from six directions:
First, acetylcholine release in the brain is related to local blood flow increases as mediated by endothelium related release of NO.
The deficits in the acetylcholine system known in AD are temporarily and partly relieved by therapy with one of the acetylcholine esterase inhibitors (e.g. donazepil or aricept).
An increase in blood flow in the brain occurs in patients receiving donazepil treatment.
In fact there is an increase in peripheral blood flow in AD patients receiving donazepil relative to controls not receiving donazepil determined from our recent studies.
The endothelial cells in the periphery as well as in the brain play an essential role in this blood flow increase.
Second, the histopathology of microvasculature in AD shows an increase in basement membrane.
Third, drugs such as nonsteroidal anti-inflammatory agents and the statins which treat diseases involving the endothelium such as inflammation and atherosclerosis, respectively, have been shown to reduce the risk of developing AD in a convincing number of studies.
Fourth, a connection between AD and endothelium pathology is implied from the measured decrease in both blood flow and metabolism in the parietal and temporal cortex, though these decreases, known for over 20 years, have been attributed to local neuronal degeneration.
Fifth, there is an abundance of observed mechanisms for angiogenesis in the AD brain.
Sixth, the AD brain endothelium secretes the precursor substrate for the β-amyloid plaque and a neurotoxic peptide that selectively kills cortical neurons.
So where do these facts leave us?
Is there a fundamental defect in brain endothelial cells?
Is there an abnormal stimulus, which leads to inflammation then abnormal angiogenesis?
Does a basic defect in acetylcholine mediated flow control result in repeated hypoxia and a resultant angiogenesis?
Is the angiogenesis merely a response to other factors such as amyloid plaque and neurofibrillary tangles as most have surmised?
Or could it be that the progenitor cells of the endothelium are themselves defective or there are not enough progenitor cells to repair the naturally senescent or damaged endothelium of the brain vasculature?
If there were a basic defect in endothelial progenitor cells would we not predict some manifestations of dysfunction in peripheral cells as well?
Evidence for Peripheral Cell Pathologies in AD Patients
Five observations give evidence for the systemic nature of AD relative to circulating blood cells and peripheral fibroblasts.
Here we focus on cells of mesenchymal origin.
First, alterations in oxidative processes have been found in nonneuronal tissues including fluids (e.g., cerebrospinal fluid, plasma and urine), cells (e.g., red blood cells platelets, lymphocytes and cultured cells such as fibroblasts).
These results are interpreted as evidence that there are inherent defects of peripheral AD cells and not some secondary effect.
The argument is not compelling as the response of bone marrow and other tissues to the release of cytokines associated with a primary pathology in the CNS could give rise to many of the observed changes in the periphery.
Second, the presence of inflammatory and immuno-related markers in the peripheral neutrophils of AD patients has also been reported.
Third, cultured skin fibroblasts have altered metabolic properties.
Fourth, among other effects is a report of a specific alteration of an intracellular pathway involved in sensing and repairing DNA damage in peripheral cells from Alzheimer's disease patients.
Fifth, T-cell telomere shortening has been found in peripheral blood cells of AD patients.
Telomeres are the repeated DNA sequences that cap chromosomes and undergo shortening with each cell division.
Thus, telomere length is related to a cell's replication history.
Telomere length is inversely correlated with pro-inflammatory cytokine TNFα concentration in AD patients.
Role of Progenitor Endothelial Cells
Until recently, it was generally thought that the formation of new vessels in adults occurred exclusively through the extension of mature existing blood vessels and the associated vascular endothelium (vasculoneogenesis).
A growing body of evidence now suggests that bone marrow-derived endothelial progenitor cells circulate in the blood and can play an important and perhaps the major role in repair and in the formation of new blood vessels in pathologic conditions.
The fact that endothelium is replaced by circulating progenitor or stem cells may come as a new perspective to biologists and medical scientists, but the evidence is compelling.
The dynamics and importance of progenitor cells in the cardiovascular system were showed by recent discovery that the progenitor cell concentration in the circulating blood is less in patients with high risk factors for atherosclerosis.
In addition to that, the investigation determined that the age distribution of the cells from both patients and control groups were similar thus ruling out the possibility that the low concentration was the result of increased consumption by the atherosclerotic lesions.
The use of autologous bone marrow stem cells (monocytes) in therapy of myocardial infarction patients after balloon angioplasty showed that after infusion of their autologous bone marrow monocytes into the coronary artery that supplied the region of the infarct, the size of the infarcted region was reduced from 30% to 12% and the wall motion velocity increased from 2 cm/sec to 4 cm/sec.
Beyond the endothelial cells there are other cells in the perivascular spaces including pericytes, microglia, T-cells, mast cells and histiocytes, which have recently been shown to arise from migratory macrophages and not resident histiocytes.
Experimentally was shown that the replacement of perivascular cells by blood-born macrophages in adult mice was complete by 14 weeks post-transplantation.
It is generally accepted that the microglia have an exclusive origin from circulating macrophages.
There is increasing evidence that microglia plays an active part in degenerative CNS diseases and in Alzheimer's disease activated microglia appears to be involved in plaque formation.
Verifying that the already known manifestations of AD in peripheral cells are primary and not secondary to metabolic and inflammatory inducements from the CNS, one can consider therapies, which range from modifications of the behavior of bone marrow progenitor cells to more radical therapies such as allogenic bone marrow transplantation and even progenitor endothelial cell infusions into the Alzheimer's brain.
Some precedence for these suggestions exists.
For example, recently study reported heart function and infarction volume reduction in patients after infusion into the region of infarction of autologous bone marrow monocytes.
This experiment was motivated by the recent acceptance that endothelial progenitor cells must play a pivotal role in atherosclerosis.
The suggestion of bone marrow transplantation comes from the extensive experience of successful allogenic bone marrow transplants in human autoimmune diseases.
Alternatively if the role of endothelial cells is compromised in their ability to prevent invasion of an infectious agent (e.g., abnormally high sensitivity to infective bacteria lipopolysaccharides) then therapies such as blockade of activated NMDA receptors or benzodiazepine receptors of activated glial cells may have promise in AD and Parkinson's disease.