Weill Cornell Physicians

Laboratory of Alzheimer's Disease Neurobiology

The goal of the laboratory is to uncover the cell biological and pathological basis of Alzheimer's disease, with the ultimate aim of contributing to novel treatment strategies for this ever more common disease of aging. The abnormal deposition of beta-amyloid peptides in the brain is the pathological hallmark of Alzheimer's disease. Cumulative evidence has linked accumulation of 42 amino acid beta-amyloid peptides to the development of Alzheimer's disease.

Several years ago, we discovered that beta-amyloid peptides begin to accumulate within vulnerable neurons in brain with aging prior to the development of the characteristic extracellular amyloid plaques (Gouras et al., 2000). We subsequently were the first to demonstrate that this aberrant accumulation of beta-amyloid occurs especially in endosomes within distal nerve cell processes and synapses, where with marked accumulation it is associated with ultrastructural evidence that is consistent with degeneration (Takahashi et al., 2002). This work led us to reevaluate the origin of Alzheimer's disease plaques and how beta-amyloid is involved in the disease process (Gouras et al., 2005). We then turned to a biological system to explore the neurobiological mechanism whereby accumulating beta-amyloid might be detrimental. We reported that neurons from Alzheimer's disease transgenic mice with time in culture develop subcellular beta-amyloid accumulation that paralleled our observations in brain (Takahashi et al., 2004) and provided the first evidence of decreases in levels of glutamate receptors, important for learning and memory, at synapses of neurons derived from Alzheimer's disease transgenic mice (Almeida et al., 2005). Evidence supported that impairment of the ubiquitin-proteasome system is involved in these beta-amyloid accumulation-induced synaptic alterations (Almeida et al. 2006). Most recently, we reported on a novel mechanism whereby beta-amyloid immunotherapy, currently a leading experimental therapy for the disease, can reduce levels of beta-amyloid and restore synapses in nerve cells derived from Alzheimer's disease transgenic mouse models (Tampellini et al., 2007).

Ongoing projects in the laboratory center on further understanding the molecular and cellular mechanisms by which the accumulation of beta-amyloid peptides in endosomal vesicles of nerve cells leads to dysfunction and later degeneration of synapses in the disease. Biochemical assays, such as immunoprecipitation and Western blot, immunofluorescence confocal microscopy, including live-cell imaging, and immuno-electron microscopy are used to investigate changes in neurons in the brain and in culture of transgenic models of Alzheimer's disease. Specific projects include elucidating the role of synaptic activity in the beta-amyloid induced synaptic alterations and the link between subcellular beta-amyloid accumulation and alterations in microtubule-associated proteins. Collaborative projects include studies on how oxidative stress promotes, and antioxidant therapy prevents, beta-amyloid accumulation and the development of Alzheimer's disease.

For further information on the laboratory, and for highly motivated applicants interested in joining the laboratory, please contact Dr. Gunnar Gouras: Telephone: (212) 746-6598

Email: gkgouras@med.cornell.edu