Citations

AbstractIntroductionCerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood‐brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases.MethodsWe performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin‐5 (CLDN5) and occludin (OCLN), and major AD‐related molecules (amyloid beta [Aβ40], Aβ42, tau, p‐tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.ResultsHigher levels of soluble tau, insoluble p‐tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.DiscussionRefining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.

Abstract Alzheimer’s disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer’s disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer’s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer’s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer’s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer’s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0–16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer’s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer’s disease and primary age-related tauopathy.

AbstractNeuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico‐based screening using whole‐genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases.

Abstract Tau is a microtubule-associated protein that promotes polymerization and stabilization of microtubules. It is the major component of fibrillary neuronal and glial inclusions in Alzheimer's disease (AD) and the tauopathies. An autosomal dominant familial tauopathy, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), has been shown to be caused by pathogenic tau mutations. Neuropathologic features of FTDP-17 are filamentous tau aggregates in neurons and glia. Previous transgenic mice carrying the normal human tau gene developed motor neuron disease and had dystrophic axons, but no neurofibrillary tangles (NFT). In this report we describe ultrastructural features of NFT in transgenic mice carrying a mutant human tau gene. The mice were generated with a tau cDNA containing exon 1, 4, 5, 7, 9, 10, 11-13, intron 13 and exon 14, driven by the mouse prion promoter (MoPrP) and containing the most common FTDP-17 mutation, P301L. The transgenic construct was generated by ligating the P301L tau cDNA with the mouse prion promoter.

Abstract Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain ageing. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b−/− mouse model. We included 10 Tmem106b+/+ (wild-type), 10 Tmem106b+/− and 10 Tmem106−/− mice. The most differentially expressed genes (153 downregulated and 60 upregulated) were identified between Tmem106b−/− and wild-type animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of OLIG2-positive cells in the corpus callosum of Tmem106b−/− mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. Quantitative polymerase chain reaction revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b−/− mice are more susceptible to cuprizone-induced demyelination and have a reduced capacity to remyelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line and primary cultured oligodendrocytes, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels.

Frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions (FTLD‐U) is the most common cause of frontal lobe dementia. Recently, the TAR DNA binding protein (TDP‐43) has been described as a marker for FTLD‐U. TDP‐43 has been reported to be specific for neuronal inclusions in FTLD‐U and not other degenerative disorders such as Alzheimer's disease (AD). The reported specificity of TDP‐43 makes it possible to detect FTLD‐U in the setting of other neurodegenerative diseases. On this assumption, we determined the frequency of FTLD‐U in AD. Additionally, since FTLD‐U is often associated with hippocampal sclerosis (HpScl), a process characterized by neuronal loss in Sommer's sector of the hippocampus, we also determined the frequency of FTLD‐U in HpScl. A series of 74 AD and 20 HpScl cases were screened with TDP‐43 immunohistochemistry. Immunoreactivity for TDP‐43 was detected in 13 of 20 (65%) HpScl cases and 42 of 74 (57%) AD cases, including 33 of 44 (75%) cases of AD with HpScl and 9 of 30 (30%) cases of AD without HpScl. The specificity of TDP‐43 was assessed by double immunolabeling for tau at the light and electron microscopic level. The frequency of tau and TDP‐43 co‐localization was 13%. At the EM level TDP‐43 immunoreactivity was present in cytosolic granular material, but some tau‐positive filaments were also labeled. The results suggest that FTLD‐U occurs frequently in HpScl and AD.

Prominent behavioral changes and language dysfunction are features of frontotemporal lobar degeneration (FTLD) but can also occur in AD. Recently, application of TAR DNA‐binding protein 43 (TDP‐43) antibody has been shown to be useful for demonstrating the pathologic lesions of FTLD‐U and FTLD‐MND. Since these cases might represent combined disorders (FTD and AD), we studied the utility of TDP‐43 staining to demonstrate inclusion bodies in brains of patients with clinical features of frontal or temporal lobe dysfunction but with autopsy features of AD. METHODS: Eight patients from 1998 to 2005 were identified, including 1 with combined pathologic features of FTLD‐U (previously identified with anti‐ubiquitin staining) and mild AD (Braak stage IV). Sections of hippocampus and frontal and temporal lobes were stained with anti‐TDP‐43 antibody (Proteintech Group). RESULTS: Of the 8 patients, 1 had advanced AD (Braak stage VI) and scattered TDP‐43 positive cytoplasmic inclusions in hippocampal dentate granular cells and frontal and temporal neocortical neurons. The previously identified patient with combined FTLD‐U and mild AD also had TDP‐43 positive cytoplasmic and nuclear inclusions. CONCLUSION: TDP‐43 aids in the identification of case with dual pathologies, particularly in advanced AD where inclusion may be masked by overwhelming AD pathology.