Robert Mahley, MD, PhD
|School||UCSF School of Medicine|
Areas of Investigation
The major focus of our laboratory is to elucidate the function of apolipoprotein (apo) E in both cardiovascular disease and neurobiology. We are especially interested in determining the basis of the differential effects of the apoE isoforms (apoE2, E3, and E4) in neuronal repair/remodeling, in neuroprotection, and in defining how apoE4 causes neuropathology.
ApoE is produced in abundance in the brain and serves as the principal lipid transport vehicle in cerebrospinal fluid. ApoE4 is a major gene associated with 60–70% of cases of sporadic and familial Alzheimer’s disease. ApoE4 increases the occurrence and lowers the age of onset of Alzheimer’s disease and is also associated with poor clinical outcome in patients with traumatic brain injury. Defining the effects of the three apoE isoforms on the structure and function of the brain is providing crucial insights into the contribution of apoE4 to neurological disease, and providing a way forward for treating Alzheimer’s disease and other apoE4-associated neurodegenerative disorders.
We use biophysical techniques in combination with cell and molecular biology, and transgenic and gene knockout mice to study the molecular mechanisms involving apoE in normal development and disease, including Alzheimer’s disease and other neurodegenerative diseases. Medicinal chemistry is used to identify small molecules that modulate the structure of the apoE4.
My laboratory described apoE’s receptor ligand function, determined its protein and gene sequences, mapped the amino acid residues involved in receptor binding, and defined the three-dimensional structure of the ligand-binding domain. Understanding the structure and function of apoE laid the groundwork for the recent explosion of studies concerning apoE4 and Alzheimer’s disease. My laboratory was involved in describing the role of apoE in lipid transport in the nervous system, modulation of mitochondrial activity, and cytoskeletal stability involving normal and pathological CNS metabolism. By establishing brain-specific apoE transgenic mice, we demonstrated detrimental effects on apoE4 on the central nervous system in vivo and described a mechanism whereby apoE4 is involved in neuropathology.
Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease. It has since emerged as a major risk factor (causative gene) for Alzheimer’s disease and other neurodegenerative disorders. Detailed understanding of the structural features of the three isoforms (apoE2, apoE3, and apoE4), which differ by only a single amino acid interchange, has elucidated their unique functions. ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors) and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors). ApoE4 also increases the risk for neurodegenerative diseases, decreases their age of onset, or alters their progression. ApoE4 likely causes neurodegeneration secondary to its abnormal structure, caused by an interaction between its carboxyl- and amino-terminal domains, called domain interaction. When neurons are stressed or injured, they synthesize apoE to redistribute cholesterol for neuronal repair or remodeling. However, because of its altered structure, neuronal apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments (12–29-kDa) that escape the secretory pathway and cause mitochondrial dysfunction and cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented by small-molecule structure correctors that block domain interaction by converting apoE4 to a molecule that resembles apoE3 both structurally and functionally. Structure correctors are a potential therapeutic approach to reduce apoE4 pathology in both cardiovascular and neurological disorders.
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