Affiliations: [a] Laboratorio de Circuitos Corticales (CTB), Universidad Politécnica de Madrid, Campus Montegancedo S/N, Pozuelo de Alarcón, Spain | [b] Instituto Cajal (CSIC), Madrid, Spain | [c] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain | [d] Center for Neural Science, New York University, New York, NY, USA | [e] Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), C/ Nicolás Cabrera 1, Campus de Cantoblanco, Universidad Autónoma de Madrid, Madrid, Spain
Correspondence:
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Correspondence to: Javier DeFelipe, Laboratorio Cajal de Circuitos Corticales (CTB), Universidad Politécnica de Madrid, Campus Montegancedo S/N, Pozuelo de Alarcón, 28223 Madrid; or Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain. Tel.: (+34) 91 452 4900, ext. 1934; E-mail: [email protected] or, Jesús Ávila, Centro de Biología Molecular “Severo Ochoa”, C/ Nicolás Cabrera 1, Campus de Cantoblanco, Universidad Autónoma de Madrid, 28049 Madrid, Spain. Tel.: (+34) 34 91 196 4564; E-mail: [email protected].
Note: [1] Both authors contributed equally this work.
Abstract: A key symptom in the early stages of Alzheimer's disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients.
