Professor Lawrence Goldstein and his lab hopes to elucidate the molecular basis of neuronal defects in Alzheimer’s disease by studying how cellular motors interact with–and control the behavior of–axonal vesicles. Source: http://www.flickr.com/photos/heartlover1717/816 8288215 /sizes/z/in/photostream/
As the concluding speaker for the 2013 Life Sciences Symposium hosted by Geisel School of Medicine, Professor Lawrence Goldstein – the director of the Stem Cell Program at UCSD – presented his lab’s research on Alzheimer’s disease. The Goldstein lab studies how cellular motors interact with – and control the behavior of – axonal vesicles and has used this understanding to elucidate the molecular basis of neuronal defects in Alzheimer’s disease (AD).
Alzheimer’s disease is the most common cause of dementia in the world. Yet more than a century following its discovery, the condition is still incurable, and the few treatments that do exist have minimal efficacy. Since the early 1990s, researchers have hypothesized that Alzheimer’s development could be attributed to beta-amyloid (Aβ) deposits in the brain. This hypothesis is supported by the fact that individuals with a 50% increase in the level of amyloid precursor protein (APP) have triple the risk of developing hereditary Alzheimer’s disease by their 30s or 40s.
However, Goldstein suggested an alternative to the beta-amyloid hypothesis by postulating that the disease cascade and the beta-amyloid deposit are initiated by hyperphosphorylation of tau proteins, which normally stabilize microtubules. When the tau proteins become over-saturated with phosphates, the condition may lead to the disintegration of the microtubules and the collapse of the neuron’s transport system. To support the tau hypothesis, Goldstein pointed to recent research that neurons in people who have Alzheimer’s have significant cytoskeletal abnormalities and that virtually every protein that have been implicated in the biochemistry and genetics of Alzheimer’s have had altered transport patterns, which led Goldstein to believe that errors in transport and trafficking occur early in Alzheimer’s disease.
To test this hypothesis, researchers increased APP levels and decreased kinesin-1 (a cellular motor protein) in the fruit fly, which led to an increased frequency of axonal blockages. These interactions between APP and kinesin-1 led to the idea that APP may compete with other neuronal cargoes for available neuronal motors like kinesin-1. Similar experiments in mouse models demonstrated that the over-expression of APP also induced axonal transport defects in the mouse. Interestingly, these blockages occur months before amyloid plaque deposits, suggesting the potential to screen for Alzheimer’s detection earlier.
However, Goldstein pointed that the use of different genetically modified animal models have led to a number of conflicting hypotheses on the initiation of Alzheimer’s disease, which is made more problematic considering that animal can only model specific symptoms of Alzheimer’s disease.
To address this problem, Goldstein’s lab studied the progression of Alzheimer’s disease in human cells by taking advantage of pluripotent stem cell lines containing mutations known to cause hereditary Alzheimer’s disease. Specifically, the researchers reprogrammed fibroblast cells from two subjects with a hereditary form of Alzheimer’s disease, two with sporadic Alzheimer’s disease, and two non-demented individuals into induced pluripotent cell lines (iPSC). These cells were then differentiated into neurons and characterized to observe for noticeable differences between cells derived from Alzheimers disease and non-patients, the latter of which served as the control.
Researchers found that neurons from patients with the hereditary form of Alzheimer’s disease recapitulated early features of the disease’s biochemistry and demonstrated a direct relationship between APP protein processing and tau phosphorylation in human neurons, thereby bolstering the tau hypothesis over the beta-amyloid hypothesis.
Goldstein demonstrated that iPSC technology can be used to observe phenotypes relevant to Alzheimer’s disease and could be applied for larger studies, provided that scientists could streamline the process of growing induced pluripotent cells. Such a method could provide greater insight into the mechanisms behind the observed heterogeneity in the progress of Alzheimer’s, patient-specific drug response, and prospective diagnostics.