Wu Z, Guo H, Chow N, Sallstrom J, Bell RD, Deane R, Brooks AI, Kanagala S, Rubio A, Sagare A, Liu D, Li F, Armstrong D, Gasiewicz T, Zidovetzki R, Song X, Hofman F, Zlokovic BV. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med. 2005 Sep;11(9):959-65. PubMed.

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  1. Prior to the 1980s, the cause of death of elderly demented individuals was commonly listed as pneumonia. In the 1980s, Alzheimer disease gained increasing attention, in part due to the tireless efforts of pathologists, such as Robert Terry, and neurologists, such as Robert Katzman. Terry and Katzman made the public and the medical community aware that senile dementia of the Alzheimer type was not the normal form of aging, was also not the normal outcome of other diseases, such as vascular diseases (hypertension, multi-infarct dementia, etc.) or diabetes, and should be listed as a principal cause of death, even when the immediate cause of death was a disease, such as pneumonia. In the intervening years, the field has advanced tremendously, and research has identified the roles of Aβ and tau, and codified the amyloid cascade hypothesis.

    Despite the mechanistic clarity provided by the amyloid cascade hypothesis, many questions remain, particularly with respect to late-onset Alzheimer disease. At the same time, increasing evidence indicates that other chronic diseases, such as hypertension, mid-life hypercholesterolemia, and diabetes, increase the incidence of AD and might contribute to the pathophysiology. The current manuscript by Wu and colleagues provides some of the molecular details that might contribute to the vascular-Alzheimer linkage. In an elegant study, they did transcriptional profiling on brain endothelial cells, and identified transcripts whose expression was not altered in normal aging but was altered in the Alzheimer brain. Among the genes is a homeobox gene, termed MEOX2, which acts as a transcription factor and regulates a number of genes that could easily be important for the pathophysiology of AD. MEOX2 regulates factors important for Aβ uptake, such as LRP1, factors important for apoptosis, such as AFX1, and factors important for capillary growth. They follow the amyloid story into genetically engineered mice, and show that mice lacking MOEX2 exhibit reduced flux of Aβ across cerebral endothelial cells. These experiments are very intriguing and provide an interesting mechanism that could link AD with vascular abnormalities. The concept of Aβ flux is also particularly appealing because this idea was highlighted by studies on passive Aβ immunization. On the other hand, MEOX2 is involved in so many different processes that it is likely only a fraction of them are truly relevant to AD. Defining how vascular abnormalities contribute to AD clearly will be a fascinating avenue of research as the field matures and is able to incorporate new mechanistic details into our understanding of late-onset AD.

    View all comments by Benjamin Wolozin

  2. Wu and colleagues, in a recent Nature Medicine paper, report a potential role for the MEOX2 hemeobox gene, also known as GAX, in Alzheimer disease. The authors cultured brain endothelial cells (BECs) from humans who died with Alzheimer disease, age-matched controls, and young controls. They found upregulation and downregulation of groups of genes in the BECs derived from AD cases. A gene that was strongly downregulated was MEOX2. Due to the previously described role of MEOX2 in angiogenesis, they further explored whether MEOX2 may have a role in brain angiogenesis. They found that in MEOX2 +/- mice, there was a decrease in cerebral blood flow and capillary length, and that vessels from these mice did not respond normally to hypoxia. Since the blood-brain barrier (BBB) is involved in amyloid-β (Aβ) efflux from the brain, they also determined whether there was a deficit in Aβ40 efflux out of the brain. A large decrease in Aβ40 was found that was consistent with a decrease in efflux mediated via BBB transport. The fact that LRP was also decreased in brain capillaries from these mice may be why there was decreased Aβ40 efflux. Overall, these results suggest that a decrease in MEOX2, if present in AD brain capillaries in situ, may be playing a role in decreased capillary density and other important changes in the AD brain that could contribute to cognitive deterioration in AD. In terms of AD pathogenesis, the authors did not observe a decrease in MEOX2 in brain capillaries from an APP transgenic mouse model that develops amyloid deposition. This suggests that the change in MEOX2 in AD may not occur as an early step in AD pathogenesis since Aβ deposition appears to occur very early in the pathogenic cascade that ultimately culminates in the cognitive changes seen in AD. Understanding whether and how certain molecules contribute to AD progression is important, and further studies to sort out whether MEOX2 contributes to AD progression are certainly warranted. It will be interesting to see if there is a change in amyloid-related pathology if MEOX2 +/- mice are bred to APP transgenic animals. It will also be interesting in future studies to know the effect of enhancing MEOX2 function in other AD-type models as well as in models of other neurodegenerative diseases.

    View all comments by David Holtzman

  3. Excellent article.

    View all comments by J. Lucy Boyd

  4. This hypothesis is old and dead. Of course hypoperfusion can increase the risk of AD, but is not shown to be strongly causative, or necessary, in amyloidosis of either the brain or other organs. Reduced blood supply to the carotid artery can, in some cases, evoke a strong immune response or be triggered by monocyte-derived cholesterol, but is not shown definitively to be a key ingredient in AD pathogenesis. Furthermore, reduced blood supply to neurons may, in many cases, have an opposite effect in that where there is lack of immunoglobulins and oxygen, Aβ42 cannot be triggered through the presenilins' control of secretase.

    View all comments by Jacob Mack

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