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Alzheimer's disease (AD) is a major neurodegenerative disease leading to dementia and cognitive impairment, and its complex symptoms and its similarity to other types of dementia make accurate diagnosis of AD challenging
Currently, there are different hypotheses about the pathogenesis of AD, including the β-amyloid deposition and hyperphosphorylated tau protein hypothesis, the cholinergic hypothesis, and the secondary injury vascular hypothesis—cerebrovascular injury (first blow) induces the accumulation of Aβ in the brain (second blow).
So a team from the Health Institute de Compostela (IDIS) in Santiago, Spain, combed through the evidence of
vascular and endothelial progenitor changes in Alzheimer's disease.
Changes and dysfunction of the cerebrovascular system are important components of the pathophysiology of AD (healthy capillaries shown in Figure 1A and AD capillaries in Figure 1B).
Thus, this process may contribute to the emergence and progression of the disease and promote neurodegeneration, inflammation, Aβ accumulation, and tau phosphorylation
Several findings through neuroimaging, postmortem brain sample analysis, and cerebrospinal fluid biomarker testing support the presence of vascular dysfunction
1 Schematic diagram of inflammatory mediator changes in healthy capillaries and AD capillaries
MRI studies have shown CNS microbleeds
in 45-78% and 25% of patients with initial AD or MCI, respectively.
Blood-brain barrier permeability has also been measured in postmortem tissues (figure 1B), where certain substances (e.
, fibrinogen, fibrin, thrombin, plasmin, albumin, or immunoglobulin) have been detected to leak from capillaries and subsequently accumulate
in the parenchyma.
Changes in angiogenesis also occur
Vascular dysregulation leads to hypoxia in the brain, which eventually leads to the upregulation of pro-angiogenic proteins in cerebral blood vessels, such as vascular endothelial growth factor (VEGF), HIF-1α, etc
These results are consistent with hypotheses of early endothelial dysfunction in the onset of AD, and in conclusion, substantial evidence supports changes
in neurovascular components in the development of AD.
It is worth noting that this vascular dysfunction begins before the development of atrophy and/or dementia and persists
in later stages.
Based on this evidence, the hypothesis
of damaging blood vessels was proposed twice.
Secondary injury vascular theory
Damage to the cerebrovascular system can be caused
by several vascular risk factors (eg, hypertension, diabetes, hypercholesterolemia, or smoking) or genetic risk factors (e.
, APOE ε 4).
The cerebrovascular system experienced several outcomes during injury (Figure 1B).
As a result, cerebral blood flow is reduced (hypoemia), leading to hypoxia in certain areas with the subsequent release of reactive oxygen species (ROS), promoting cellular damage due to oxidative stress, and inducing the expression
In addition, HIF-1α increases the expression and activity of β-secretase and the activity
Therefore, this increases the amyloid production pathway and ultimately Aβ production
There are also dysfunctions of BBBs, leading to increased permeability of toxic molecules and their accumulation in the brain parenchyma, some of which cause neurodegeneration and further increase damage to the cerebrovascular system, and finally, cerebrovascular dysfunction triggers inflammation, defects in Aβ clearance in the brain, and increased
peripheral Aβ inflow through BBB.
Endothelial progenitor cells and their potential role in Alzheimer's disease
Since angiogenesis and BBB integrity are critical to the development of AD, and EPC is essential during endothelial repair, EPC may play a key role
in this disease.
Intravenous injection of e-EPC into rats with repeated scopolamine (SCO)-induced cognitive impairment resulted in improved learning and memory, decreased Aβ plaque deposition, suppression of Aβ and p-tau levels, and reversal of neurotransmitter abnormalities
L-EPCs were also injected intravenously into APP/PS1 transgenic mice, and exogenous EPCs had enhanced
brain penetration compared to controls.
Subsequently, using the same transgenic mouse model, EPC was injected directly into the
Transplantation of EPCs upregulated tight junction protein expression in BBB, increased microvascular density and promoted angiogenesis
in the hippocampus and cortex.
EPCs also exert anti-apoptotic effects, promoting neuronal survival
in the hippocampus.
In addition, a decrease
in the area and intensity of Aβ plaques in the hippocampus and cerebral cortex was observed.
In addition, the learning and memory abilities of AD mice (APP/PS1) were significantly improved after EPCs transplantation (see Table 1 for details).
Therefore, the use of transfected EPCs has been proposed as a possible therapeutic pathway for AD, as they can take advantage of their ability
to hom to damaged BBBs.
Table 1 Summary of relevant preclinical and clinical studies on the association between EPC and AD
In summary, given the above data, the authors conclude that there are several vascular and angiogenic alterations in AD, and EPC may play a key role
in AD-associated endothelial and BBB dysfunction.
In addition, in vivo studies using EPCs as therapeutic therapies have opened up a possible new avenue
for the treatment of AD.
However, further research is needed to confirm the potential critical role of EPC as a biomarker for early diagnosis and treatment of AD and to elucidate the underlying mechanisms
associated with the therapeutic properties of EPC.