Goal-This study aimed to determine the frequency of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) in the setting of hippocampal sclerosis (HpScl) and Alzheimer's disease (AD) using immunohistochemistry for TAR DNA binding protein 43 (TDP-43), a putative marker for FTLD-U.Methods-Initially, 21 cases of HpScl associated with a variety of other pathologic processes and 74 cases of AD were screened for FTLD-U with TDP-43 immunohistochemistry. A confirmation study was performed on 93 additional AD cases. Specificity of TDP-43 antibodies was assessed using double immunolabeling confocal microscopy, immunoelectron microscopy and biochemistry.Results-TDP-43 immunoreactivity was detected in 71% of HpScl and 23% of AD cases. Double immunostaining of AD cases for TDP-43 and phospho-tau showed that the TDP-43 immunoreactive inclusions were usually distinct from neurofibrillary tangles. At the ultrastructural level TDP-43 immunoreactivity in AD was associated with granular and filamentous cytosolic material and only occasionally associated with tau filaments. Western blots of AD cases revealed a band that migrated at a higher molecular weight than normal TDP-43 that was not present in AD cases without TDP-43 immunoreactivity.Interpretation-The present results suggest that as many as 20% of AD cases and more than 70% of HpScl cases have pathology similar to that found in FTLD-U. Whether this represents concomitant FTLD-U or is analogous to colocalization of α-synuclein and tau in AD, reflecting a propensity for co-deposition of abnormal protein conformers, remains to be determined. KeywordsAlzheimer's disease; biochemistry; electron microscopy; frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U); hippocampal sclerosis; immunohistochemistry; TAR DNA binding protein 43

Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as ‘tau propagation’ and may explain the stereotypic progression of tau pathology in the brains of Alzheimer’s disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1254-6) contains supplementary material, which is available to authorized users.

Progranulin (PGRN) is involved in wound repair

Rrecent studies have highlighted a group of 4-repeat (4R) tauopathies that are characterised neuropathologically by widespread, globular glial inclusions (GGIs). Tau immunohistochemistry reveals 4R immunore-active globular oligodendroglial and astrocytic inclusions and the latter are predominantly negative for Gallyas silver staining. These cases are associated with a range of clinical presentations, which correlate with the severity and distribution of underlying tau pathology and neurodegeneration. Their heterogeneous clinicopathological features combined with their rarity and under-recognition have led to cases characterised by GGIs being described in the literature using various and redundant terminologies. In this report, a group of neuropathologists form a consensus on the terminology and classification of cases with GGIs. After studying microscopic images from previously reported cases with suspected GGIs (n = 22), this panel of neuropathologists with extensive experience in the diagnosis of neurodegenerative diseases and a documented record of previous experience with at least one case with GGIs, agreed that (1) GGIs were present in all the cases reviewed; (2) the morphology of globular astrocytic inclusions was different to tufted astrocytes and finally that (3) the cases represented a number of different neuropathological subtypes. They also agreed that the different morphological subtypes are likely to be part of a spectrum of a distinct disease entity, for which they recommend that the overarching term globular glial tauopathy (GGT) should be used. Type I cases typically present with frontotemporal dementia, which correlates with the fronto-temporal distribution of pathology. Type II cases are characterised by pyramidal features reflecting motor cortex involvement and corticospinal tract degeneration. Type III cases can present with a combination of frontotemporal dementia and motor neuron disease with fronto-temporal cortex, motor cortex and corticospinal tract being severely affected. extrapyramidal features can be present in Type II and III cases and significant degeneration of the white matter is a feature of all GGT subtypes. Improved detection and classification will be necessary for the establishment of neuropathological and clinical diagnostic research criteria in the future.