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Blood Brain Barrier

Characterization and use of human brain microvascular endothelial cells to examine β-amyloid exchange in the blood-brain barrier. Bachmeier C, Mullan M, Paris D.

Alzheimer's disease (AD) is characterized by excessive cerebrovascular deposition of the β-amyloid peptide (Aβ). The investigation of Aβ transport across the blood-brain barrier (BBB) has been hindered by inherent limitations in the cellular systems currently used to model the BBB, such as insufficient barrier properties and poor reproducibility. In addition, many of the existing models are not of human or brain origin and are often arduous to establish and maintain. Thus, we characterized an in vitro model of the BBB employing human brain microvascular endothelial cells (HBMEC) and evaluated its utility to investigate Aβ exchange at the blood-brain interface. Our HBMEC model offers an ease of culture compared with primary isolated or coculture BBB models and is more representative of the human brain endothelium than many of the cell lines currently used to study the BBB. In our studies, the HBMEC model exhibited barrier properties comparable to existing BBB models as evidenced by the restricted permeability of a known paracellular marker. In addition, using a simple and rapid fluormetric assay, we showed that antagonism of key Aβ transport proteins significantly altered the bi-directional transcytosis of fluorescein-Aβ (1-42) across the HBMEC model. Moreover, the magnitude of these effects was consistent with reports in the literature using the same ligands in existing in vitro models of the BBB. These studies establish the HBMEC as a representative in vitro model of the BBB and offer a rapid fluorometric method of assessing Aβ exchange between the periphery and the brain.

or more information on the Roskamp Institute and Alzheimer’s please visit:

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Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier.

Several large population-based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. To determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer Aβ peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aβ production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro, whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aβ clearance across the blood-brain barrier (BBB), whereas amlodipine and nifedipine were ineffective showing that the Aβ-lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Aβ burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice, and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity, but rely on their ability to lower brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the BBB.

or more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier.

Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer's disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease.

for more information on the Roskamp Institute and Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

http://www.michaelmullan.us

www.rfdn.org

Family History of Alzheimer's disease - what does it mean?

Frequently in the Roskamp institute Memory Clinic we are asked what a family history of Alzheimer’s disease means for the children and other blood relatives of sufferers. Although this question is always handled on an individual basis there are some general guidelines that can be offered to access risk for the disease to children and other family members related to a sufferer. Naturally, family members who perceive they are at risk for developing the disease themselves may suffer from a great degree of anxiety it is therefore important to ask the staff at the Roskamp Institute what the individual risk is for developing the disease. In general the genetic risk for Alzheimer’s disease can be divided into two categories; early onset familial disease which is highly genetic and occurs in families which may have onsets of the disease in the 40s,50s or 60s; late onset disease which is frequently familial but where the disease onsets in the seventh decade onwards. We shall consider these two scenarios separately.

Early onset Alzheimer’s disease.

The term “early onset Alzheimer’s” is frequently misunderstood or used in a confusing way. What we generally mean by early onset Alzheimer’s is Alzheimer’s that onsets before the age to 60 years. This is in contrast to the term early onset as referencing the early stage of the disease. This is a confusing way to use the term and is discouraged. Early stage disease is a better term to describe the early phases of the disease. Early onset familial disease occurs in families that are affected in multiple generations by mutations in genes that can trigger the disease. Families of early onset disease thankfully are very rare but they have provided great insight into the disease process probably in all cases of the disease (early and late onset). Sadly, frequently in these families the disease is inherited in what is known as an autosomal dominant fashion. Autosomal dominant inheritance means that 50% of the offspring of each generation on average are impacted by the disease. Some generations may be very fortunate and although they may be at risk for inheriting the diseased gene from one or the other parent none of the siblings in a sibship may be affected. On the contrary sibships can be very unlucky in which case more than 50% are impacted with the disease. For each child of an affected parent there is a 50% chance of inheriting the disease and this chance is not influenced by whether other siblings have already inherited the disease or not.

Unfortunately the inheritance of these rare genetic variance means that individuals at risk are highly likely to develop the disease if they live long enough. One of the important characteristics of these familial mutations is that the disease tends to onset around approximately the same time of life. Thus if a family has a mean (average) age of onset of 52 and one inherits one of these rare generic errors then one is unlikely to live to 60 without developing signs or symptoms of the disease. By contrast if one does not carry the mutation then there is no more risk for the disease than the general population.

Again it is most important to emphasize that such families are extremely rare and early onset Alzheimer’s is not the most likely reason for patients or their families to visit the Roskamp Institute Clinic. In fact, approximately 1% or less of cases of Alzheimer’s Disease have what can be described as early onset disease. In the past, individuals who come from such families have sought genetic counseling including genetic testing for these genetic errors. It is relatively straightforward to detect such errors but clearly the genetic information is highly sensitive. Family members should therefore think very carefully before seeking such information however initially finding out more about early onset disease is a recommended step.

Clinicians at the Roskamp Institute are happy to discuss early onset disease with patients and their families as they wish. Finally it should be noted that many cases of early onset disease occur without a family history. Thus individuals can manifest the disease before the age of 60 but have no other known family members either in the prior generations or in subsequent generations that develop the disease the cause of early onset Alzheimer’s that is not familial is not well understood but importantly there is no risk to subsequent family members for development of the disease.

Late onset (common) Alzheimer’s disease. Much more commonly patients and their families come to the clinic at the Roskamp Institute and seek advice on the inheritance of Alzheimer’s when one or more members of the family has late onset disease. This is defined as disease which onsets over the age of 60 and this is by far in a way the most common cause of the disease. It is estimated that approximately 4 million Americans presently either have the disease or are in the early or pre clinical stages - most of these cases are late onset Alzheimer’s Disease. The predicted numbers for future disease prevalence are very high. For instance it is estimated that by mid century there could be as many as two hundred million individuals afflicted with the disease.

Most late onset Alzheimer’s disease does not exhibit a clear autosomal dominant pattern meaning that the risk to offspring of individuals suffering with the disease is usually considerably less than 50%. Certain genetic risk factors for late onset disease have been identified - the most important of which is apolipoprotein E (APOE). There are 3 common forms of APOE: E2, E3 and E4. The discovery by Allen Roses and his colleagues at Duke University showed that Alzheimer’s disease sufferers were much more likely to carry one or two copies of the E4 allele (genetic form) of APOE than the normal population. Carrying one copy of APOE 4 increases ones risk for the disease by approximately three times and carrying two copies can increase the risk for the disease by up to fifteen times compared to individuals who do not carry an APOE 4 allele.

Many family members express interest in being genetically tested for their risk for the disease. Such tests are commercially available but most centers discourage the use of testing prior to symptoms because many individuals who carry an APOE 4 allele do not necessarily develop the disease at least until late old age. Conversely it’s very possible to develop Alzheimer’s disease without carrying an APOE 4 allele. Therefore on an individual basis the test is not overly helpful in specifying who may or may not develop the disease. However on a group basis APOE genetic testing is very helpful to give an average estimate of the numbers of individuals who will subsequently develop Alzheimer’s.

It is anticipated that as better treatments are available for Alzheimer’s disease there will be greater interest in genetic testing. For instance it is expected that as treatments are used earlier and earlier in the stages of the disease that individuals in the very early stage or maybe with no symptoms at all might seek medical treatment once such treatment has been established as effective in stopping the rate of progression or disease onset.

Despite the fact that genetic testing is not used frequently in clinical practice it is a tremendous tool in assisting researchers in understanding when and why the diseases develops and in planning clinical trials to take into account who is most likely to develop the disease. Already there is evidence from several clinical trials that individuals that carry the APOE 4 allele may be more refractory to certain treatments. As drug development progresses it will be important to develop medications that are able to tackle the severest form of the disease i.e. those patients who are carrying and APOE 4 allele.

Summary: The two types of familial Alzheimer’s disease differ in the risk for offspring of developing the disease. The early onset cases as noted have children that are highly at risk for developing the disease if there is a family history. By contrast late onset disease or low clustering in families is much less genetically predisposed. In both cases genetic tests are available but are generally discouraged particularly for late onset disease. Roskamp Institute researchers and clinicians are well versed in the genetic aspects of the disease and can advise on an individual or family basis as required.

The Roskamp Institute is a not-for-profit research Institute located in Sarasota and Tampa, Florida, that is dedicated to understanding the causes of, and finding cures for, neuropsychiatric and neurodegenerative disorders and addictions with an emphasis on Alzheimer’s disease. The Institute’s Memory Clinics also offer comprehensive cognitive and medical assessment toward differential diagnosis of Alzheimer’s disease and offers treatments and disease management options once the diagnostic evaluation is complete

By Dr. Michael Mullan, Director of Alzheimer Research Institute, The Roskamp Institute

for more information on Alzheimer’s please visit:

http://www.mullanalzheimer.com

http://www.mullanalzheimer.info

ß-amyloid exchage in the blood-brain barrier

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