Acta Neuropathol (2007) 113:63–73 DOI 10.1007/s00401-006-0159-4 123 ORIGINAL PAPER Relation of hippocampal phospho-SAPK/JNK granules in Alzheimer’s disease and tauopathies to granulovacuolar degeneration bodies Sarita Lagalwar · Robert W. Berry · Lester I. Binder Received: 10 July 2006 / Revised: 26 September 2006 / Accepted: 12 October 2006 / Published online: 7 November 2006  Springer-Verlag 2006 Abstract Protein misfolding is a distinguishing feature of a number of neurodegenerative diseases. Accumula- tion of misfolded protein often results in cellular lesions, the location of lesions correlating with the nature of symptoms. Alzheimer’s disease (AD), Pro- gressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD) and Pick’s Disease (PiD) all pres- ent with pathological lesions containing hyperphosph- orylated Wlamentous tau protein; however, the location and type of lesion varies. In addition, granulovacuolar degeneration (GVD) bodies have been reported within hippocampal pyramidal neurons in AD, PSP, CBD and PiD tissue. GVDs are deWned as electron-dense granules within double membrane-bound cytoplasmic vacuoles. We have previously reported that the phosphorylated form of stress-activated protein kinase/c-Jun N-termi- nal kinase (p-SAPK/JNK) accumulates in granules within hippocampal pyramidal cell bodies in AD tissue at the time that hyperphosphorylated tau begins to aggregate into early-stage NFTs. We now report that p- SAPK/JNK granules are found within the hippocampal CA1 region of PSP, CBD and PiD cases as well and that these granules are likely GVD bodies. Quantitatively, p-SAPK/JNK granules and GVDs are found in compa- rable numbers of CA1 cells. Within cells, p-SAPK/JNK granules are distributed throughout the cytoplasm in a manner similar to the distribution of GVDs and a sub- set of granules co-localize with GVD markers. Ultra- structurally, p-SAPK/JNK granules are located in large cytoplasmic vacuoles, thereby Wtting the deWnition of a GVD body. With the implication of granular p-SAPK/ JNK as a marker of GVDs, our study strongly suggests that a heterogeneous group of proteins form GVDs. The mechanism of GVD formation is therefore an interesting one, and is likely separate and distinct from the mechanism of tau inclusion formation. Keywords SAPK/JNK · Tau protein · NFTs · GVDs · Alzheimer’s disease · Tauopathies Introduction Neurodegenerative disorders are typically character- ized by distinct pathological lesions that are located in speciWc brain regions. In Alzheimer’s disease (AD), hyperphosphorylated tau protein aggregates intraneur- onally to form neuroWbrillary tangles (NFTs), neuropil threads and the neuritic component of plaques [54] and is accompanied by extracellular beta amyloid plaques [37]. The anatomical localization of tau pathology in AD closely correlates with the progression of neuronal loss [8] from transentorhinal cortex to limbic cortex to neocortex [41]. In contrast, tau pathology in progres- sive supranuclear palsy (PSP) and corticobasal degen- eration (CBD) is primarily found in frontal cortex, brainstem and striatal tissue. In addition to neuronal pathology which includes some NFTs reminiscent of those in AD as well as globose tangles, tau Wlaments S. Lagalwar (&) · R. W. Berry · L. I. Binder Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, USA e-mail: s-lagalwar@northwestern.edu R. W. Berry · L. I. Binder Cognitive Neurology and Alzheimer’s Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA