Alzheimer's disease (AD) is the most common cause of dementia in the elderly, afflicts 1 in 8 elderly Americans, and care for AD patients incurs diret costs of approximately $200 billion annually. There is currently no effective therapy to delay AD onset or slow AD progression. Therefore, it is of critical importance to develop a better understanding of AD pathogenesis in order to develop new targets for therapeutic intervention. AD is characterized by the deposition of aggregated forms of amyloid (A?) plaques within the brain, which is hypothesized to be a critical instigator of synaptic loss and neurodegeneration. The strongest genetic determinant for the development of the most common form of AD, late onset AD, is possession of the apolipoprotein E 4 allele (APOE4). ApoE is a critical lipid transport protein in the CNS where it is expressed mainly by astrocytes. There are three common apoE variants (apoE2, apoE3, and apoE4) which differentially regulate A? clearance from the CNS and A? plaque formation. Little is known about the physiological regulation of apoE within the CNS, particularly in regard to the regulation of the levels and lipidation of the extracellular pool of apoE. We recently developed a method to measure the level and lipidation state of apoE directly from the brain parenchyma interstitial fluid (ISF) using in vivo microdialysis. Since neurons rely upon apoE to supply lipids and cholesterol to support neuronal function, we decided to test whether synaptic activity modulated apoE within the brain. Our preliminary data indicate that increasing synaptic activity increases the ISF level of apoE. Interestingly, synaptic activity has previously been shown to regulate A? production and A? ISF level. Therefore, we propose use in vivo microdialysis to investigate whether synaptic activity co-regulates apoE and A? within the ISF, and whether synaptic activity-dependent regulation of apoE level and lipidation impacts fluctuations in A? levels during physiological changes in neuronal activity, such as during the sleep- wake cycle. The results of our experiments will further our understanding of apoE regulation within the CNS and could provide insight for the development of novel AD therapies to reduce the burden of neurological disease.
A recent report from the Alzheimer's Association found that 1 in 8 older Americans suffer from Alzheimer's disease (AD), which is currently the 6th leading cause of death in the United States. There is currently no effective treatment to delay AD onset or slow AD progression. The direct cost of skilled care for AD patients totals nearly $200 billion annually, and is projected to increase to $1.1 trillion by 2050. Thus, it is imperative that we develop therapeutics that can prevent or treat AD. Genetic differences in apolipoprotein E (apoE), an important lipid regulator in the brain, are strongly associated with the development and progression of AD. This project will investigate how apoE contributes to AD, which may lead to a better understanding of AD and ultimately development of new AD therapies.
|Ulrich, Jason D; Finn, Mary Beth; Wang, Yaming et al. (2014) Altered microglial response to AÎ² plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener 9:20|