Citations 3
P3‐251: Magnetic resonance biomarkers of neurodegeneration in a transgenic mouse model of Alzheimer's disease
Chamberlain, Ryan , Preboske, Gregory M., Polk, Avery , Kotilinek, Linda, Wengenack, Thomas M., Poduslo, Joseph F., Youdas, S.A., Marjańska, Małgorzata , Ashe, Karen H. , Garwood, Michael , Jack, Clifford R.
Alzheimer's & Dementia | July 11, 2010 | Volume: 6 | Issue: 4S_Part_17 | Pages: No page available
Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity
Ma, Huifang, Lesné, Sylvain , Kotilinek, Linda, Steidl‐Nichols, Jill, Sherman, Mathew A. , Younkin, Linda H., Younkin, Steven G. , Forster, Colleen L. , Sergeant, Nicolas , Delacourte, André, Vassar, Robert , Citron, Martin , Kofuji, Paulo , Boland, Linda M. , Ashe, Karen H.
Proceedings of the National Academy of Sciences | April 30, 2007 | Volume: 104 | Issue: 19 | Pages: 8167-8172
The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid-β protein (Aβ), which forms amyloid plaques in Alzheimer's disease (AD), secreted APPα (sAPPα) which enhances memory, and the APP intracellular domain (AICD), which has been implicated in the regulation of gene transcription and calcium signaling. The β-site APP cleaving enzyme 1 (BACE1) cleaves APP in an activity-dependent manner to form Aβ, AICD, and secreted APPβ. Because this neural activity was shown to diminish synaptic transmission in vitro [Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) Neuron 37:925–937], the prevailing notion has been that this pathway diminishes synaptic function. Here we investigated the role of this pathway in vivo . We studied transgenic mice overproducing APP that do not develop AD pathology or memory deficits but instead exhibit enhanced spatial memory. We showed enhanced synaptic plasticity in the hippocampus that depends on prior synaptic activity. We found that the enhanced memory and synaptic plasticity are abolished by the ablation of one or both copies of the BACE1 gene, leading to a significant decrease in AICD but not of any other APP cleavage products. In contrast to the previously described negative effect of BACE1-mediated cleavage of APP on synaptic function in vitro , our in vivo work indicates that BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity.
Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
SantaCruz, Karen S., Lewis, Jada , Spires‐Jones, Tara L. , Paulson, Jennifer , Kotilinek, Linda, Guimaraes, Aaron, DeTure, Michael , Ramsden, M., Forster, Colleen L. , Yue, Mei, Orne, Jennifer D., Janus, Christopher , Mariash, Ami, Kuskowski, Michael A., Ashe, Karen H. , Ingelsson, Martin , McGowan, Eileen , Hyman, Bradley T. , Hutton, M.
Science | July 14, 2005 | Volume: 309 | Issue: 5733 | Pages: 476-481
Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.