Steven M. Paul   Adjunct Professor of Neuroscience

The research laboratory of Dr. Steven Paul, who is also the Director of the Helen & Robert Appel Alzheimer’s Disease Research Institute, seeks to better define the underlying pathogenesis of Alzheimer’s disease (AD). How do the genes known to greatly influence the risk of developing the most common form of late-onset AD (and the proteins they encode) actually contribute to the subsequent molecular and cellular events leading to the neuropathological signatures of the disease, namely amyloid plaques and neurofibrillary tangles? The latter subsequently leads to the neurodegeneration that typifies the disease and ultimately the dementia and other signs and symptoms of AD.

Dr. Paul’s research has helped shed light on genetic factors that dramatically increase risk for Alzheimer’s and actually cause the brain abnormalities that lead to the loss of neurons and the symptoms of the disease. The work of Dr. Paul and his laboratory team has focused on the most common genetic risk factors for late onset AD, the apolipoprotein E (apoE) alleles. ApoE4 carriers have a 3-15 fold greater risk for developing AD (heterozygotes and homozygotes respectively) and apoE2 is a known protective allele, reducing risk by approximately 50 percent. How do these two apoE alleles, which differ by only two codons/amino acids, so dramatically alter the risk to develop AD?

Over the past 15 years, Dr. Paul’s laboratory, in collaboration with several other laboratories, has shown that apoE4 is a major determinant of brain-amyloid burden in vivo. Using a series of transgenic mouse models, the researchers have shown agedependent and apoE isoform-dependent (E4>E3>E2) increases in brain amyloid burden that closely recapitulates what is observed in AD patients. More recent work in the Paul laboratory has shown that the brain levels of amyloid-β-peptides (Aβ), which form amyloid plaques, are greatly influenced by the apoE isoform expressed (E4>E3>E2) and that soluble brain levels of Aβ are already increased at a very early age and then continue to increase in an apoE isoform- and age-dependent manner. The apoE isoform-dependent changes in brain Aβ levels are due to apoE isoform dependent-alterations in local Aβ metabolism and clearance (E4>E3>E2) and appear to involve differential metabolism of Aβ by microglia and astrocytes.

Using a series of transgenic mouse models, the researchers have shown age-dependent and apoE isoform-dependent (E4>E3>E2) increases in brain amyloid burden that closely recapitulates what is observed in AD patients.

In related work, Dr. Paul and his research team have shown that microglia and macrophages metabolize Aβ in an apoE isoform-dependent manner via a novel C-terminal peptidase among other proteases. Their data help to explain recent PET neuroimaging findings in elderly patients at high genetic risk for AD which show early apoE isoform-dependent accrual of Aβ in brain and the formation of amyloid plaques many years before the onset of AD. Finally, their most recent data suggest an important role of apoE4 in the formation of tau aggregates and neurofibrillary tangles, the other major neuropathological hallmark of AD. Their findings have both diagnostic and therapeutic implications and both are being actively pursued.

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Contact

full name

  • Dr. Steven M. Paul

primary email

  • stp2015@med.cornell.edu

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Primary Affiliation

  • Weill Cornell Medical College, Cornell University