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The most common genetic risk factor for Alzheimer’s disease (AD) disrupts the blood brain barrier, impeding oxygen and nutrient flow to the brain and exposing the brain to systemic toxins, according to a recent investigation led by scientists from the University of Rochester Center for Neurodegenerative and Vascular Brain Disorders .
Apolipoprotein E (ApoE), a lipid binding protein that plays a central role in cholesterol metabolism, occurs in three different forms or alleles, E2, E3, and E4. The E4 allele is associated with significantly increased risk of late onset AD, and is found among 40% of all AD subjects. Inheritance of two E4 alleles carries with it a 90% risk of AD. In contrast, the E3 allele has no influence on risk of developing AD, while the rare E2 allele confers a limited protection against this disease .
In the current study, published in the journal Nature, scientists used mice transgenic for the three different ApoE alleles to demonstrate that the E4 allele activates a pro-inflammatory pathway leading to the activation of enzymes that destroy the molecular scaffold that supports the blood brain barrier (BBB), leading to vascular defects .
In this study, different mouse strains were established with targeted replacement of the endogenous mouse ApoE gene with each of the three human ApoE alleles. Expression of the E4 allele, but not the E2 or E3 allele resulted in breakdown of the BBB as shown by the movement of labeled high molecular weight proteins from the blood stream into the brain. In E4 expressing animals, levels of the pro-inflammatory signal molecule cyclophilin A (CypA) were found to be elevated in cerebral blood vessels. CypA is known to work via nuclear factor kappa-B (NF-kappa-B)to stimulate matrix metalloproteinases which dissolve the matrix proteins that would normally hold cells in close apposition to form a barrier to molecules exiting the blood stream. Scientists reported evidence for the activation of this pathway, and demonstrated that knockout of the CypA gene, or inhibition of CypA with drugs prevented the breakdown of the BBB in the presence of the E4 allele.
The BBB is the physical, chemical and immunological separation of the central nervous system from the circulating blood, and this barrier is essential for the normal function of the brain. Breakdown of the barrier may elicit auto-immune diseases such as multiple sclerosis, and may leave the brain susceptible to a host of circulating proteins which may be toxic to nerve cells. The blood brain barrier (BBB) not only prevents influx of toxins into the brain, it is responsible for the clearance of toxins from the brain such as the neurotoxic peptide that is believed to play a central role in pathogenesis in AD, the Alzheimer’s A-beta peptide. The BBB is increasingly being viewed as a therapeutic target for drugs which might increase the transport of such toxins .
Although the link between ApoE and AD has been long established, the molecular basis for the link remains uncertain. Because of its role in lipid metabolism, ApoE has been viewed as the nexus between cardiovascular risk factors and AD. Carriers of the E2 allele are at increased risk of type III hyperlipoproteinemia — a genetic disorder characterized by accumulation of remnant lipoproteins in the plasma and development of premature atherosclerosis — while carriers of the E4 allele have increased plasma cholesterol levels and face an elevated risk for coronary heart disease. Also, ApoE is a transporter of A-beta, and is reported to play a role in the proteolysis and clearance of A-beta, with the E4 allele being the least active in these functions . However, the E4 allele of ApoE promotes aggregation of A-beta peptide into amyloid, forming some of the characteristic pathological lesions of the disease, including senile plaques and vascular amyloid angiopathy. The E4 allele is also associated with increased risk for developing other neurodegenerative diseases such as Parkinson’s disease, and with poorer prognosis for traumatic brain injury patients. This study suggests that pharmacological targeting of the CypA pathway may be beneficial for these diseases.
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