While post mortem studies have identified the major cell types and functional systems affected in Alzheimer’s disease (AD) the initial sites and molecular characteristics of pathology are still unclear. Because individuals with Down syndrome (DS) (trisomy 21) develop the full pathological changes of AD in a predictable way by the time they reach middle to late age, a study of the brains of such persons at different ages makes an ideal ‘model system’ in which the sites of earliest onset of pathology can be detected and the subsequent progression of changes be monitored. In the present study we have examined the brains of 56 individuals with DS ranging from new-born to 76 years for the presence of amyloid and tau pathology in key cortical and subcortical regions. Amyloid pathology was found to commence in the late teens to twenties as a deposition of diffuse plaques initially within the temporal neocortex, quickly involving other neocortical regions but only reaching subcortical regions and cerebellum by the late forties. Cerebral amyloid angiopathy did not regularly commence until after 45–50 years of age. Tau pathology usually commenced after 35 years of age, initially involving not only entorhinal areas and hippocampus but also subcortical regions such as locus caeruleus (LC) and dorsal raphe nucleus (DRN). Later, tau pathology spread throughout the neocortex reaching occipital lobes in most instances by mid-50 years of age. Such a pattern of spread is consistent with that seen in typical AD. We found no evidence that tau pathology might commence within the brain in DS before amyloid deposition had occurred, but there was limited data that suggests tau pathology in LC or DRN might predate that in entorhinal areas and hippocampus or at least be coincident.

Type II Diabetes Mellitus (T2D) is a protein misfolding disorder and a major non-genetic risk factor for sporadic Alzheimer's disease (AD). In T2D large deposits of the amyloidogenic pancreatic hormone amylin form in the pancreatic islets - leading to inflammation and cell death. The literature reports presence of deposits of amylin in the cerebral vasculature of AD patients and indicates this is from peripheral production in the pancreas. We have investigated these findings and ways in which amylin may contribute to AD pathology. Brain samples from control and AD cases with and without comorbid T2D were obtained from the Manchester Brain Bank for this study (with occipital grey matter and temporal grey and white matter from each). The presence of amylin was assessed by immunohistochemistry and quantified by ELISA following homogenisation and fractionation of occipital and temporal brain sections. The effects of synthetic monomers and oligomers of amylin were assessed in neurons derived from induced pluripotent stem cells (iPSCs). Western blotting, ELISA and mesoscale analysis were used to measure the effects of amylin on Aß production and degradation and on markers of autophagy. Human occipital grey matter was also used to investigate IAPP (amylin precursor) gene expression by RT-PCR. Immunohistochemistry demonstrated amylin deposits in the vasculature of brain tissue. Investigation of effects of amylin on iPSC derived neurons demonstrated an increase in extracellular Aβ levels. Mesoscale assay of levels of sAPPα and sAPPβ in media demonstrated no increase in either soluble fragment. This result implies that amylin increases extracellular Aß without influencing cleavage of APP. Our investigation of the potential mechanisms causing increased extracellular Aß suggests amylin may impair autophagy. RT-PCR data demonstrated expression of IAPP gene in human brain fractions and this was upregulated in AD cases. Our results confirm deposition of amylin in cerebral vasculature and provide new data to suggest amylin may be produced by brain tissue. Amylin appears to contribute to AD by increasing cerebral Aβ via impairment of autophagy-mediated Aß degradation. The results of this study provide further evidence for amylin as a link between T2D and AD.

Aims: Microglia-driven neuroinflammation can play an important role in the pathophysiology of neurodegenerative disorders. In this study, we sought to characterize the distribution of microglial cell activation in 2 neurodegenerative dementias with distinct protein signatures, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) of the TDP subtype, and to determine if there was an anatomical correlation with the phenotypes most commonly associated with these conditions. Methods: The distribution and extent of microglial cell activation was assessed semiquantitatively in the hippocampal formation, cortical gray matter, and subcortical white matter of CD68-immunostained sections of the frontal, temporal, parietal, and occipital cortices from 15 pathologically confirmed cases of AD, 13 cases of FTLD, and 18 controls. Results: Significantly higher levels of microglial cell activation occurred in the subiculum in AD and FTLD than in controls. Additionally, AD had higher microglial activation in the CA1 and FTLD in the hippocampal white matter than the controls. Microglial activation was greater in the dentate gyrus molecular layer in AD than in FTLD. In the cortical regions, the 2 pathological groups differed only in frontal white matter, with the FTLD group showing higher microglial scores. FTLD showed higher microglial activation in the white matter compared to the respective gray matter in the entorhinal, temporal, and frontal regions. Conclusions: Our work expands the knowledge of the distribution and magnitude of microglial activation in these disorders. Additionally, we found some microglial circuit-specific patterns that could help to explain some of the clinical overlap between AD and FTLD-TDP, namely in memory deficits.

Huntington's disease (HD) is a fatal autosomal-dominant neurodegenerative disorder that affects approximately 3-10 people per 100 000 in the Western world. The median age of onset is 40 years, with death typically following 15-20 years later. In this study, we biochemically profiled post-mortem frontal lobe and striatum from HD sufferers (n = 14) and compared their profiles with controls (n = 14). LC-LTQ-Orbitrap-MS detected a total of 5579 and 5880 features for frontal lobe and striatum, respectively. An ROC curve combining two spectral features from frontal lobe had an AUC value of 0.916 (0.794 to 1.000) and following statistical cross-validation had an 83% predictive accuracy for HD. Similarly, two striatum biomarkers gave an ROC AUC of 0.935 (0.806 to 1.000) and after statistical cross-validation predicted HD with 91.8% accuracy. A range of metabolite disturbances were evident including but-2-enoic acid and uric acid, which were altered in both frontal lobe and striatum. A total of seven biochemical pathways (three in frontal lobe and four in striatum) were significantly altered as a result of HD. This study highlights the utility of high-resolution metabolomics for the study of HD. Further characterization of the brain metabolome could lead to the identification of new biomarkers and novel treatment strategies for HD.

Intracellular filamentous tau pathology is the defining feature of tauopathies, which form a subset of neurodegenerative diseases. We have analyzed pathological tau in Alzheimer’s disease, and in frontotemporal lobar degeneration associated with tauopathy to include cases with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and ones due to intronic mutations in MAPT . We found that the C-terminal band pattern of the pathological tau species is distinct for each disease. Immunoblot analysis of trypsin-resistant tau indicated that the different band patterns of the 7–18 kDa fragments in these diseases likely reflect different conformations of tau molecular species. Protein sequence and mass spectrometric analyses revealed the carboxyl-terminal region (residues 243–406) of tau comprises the protease-resistant core units of the tau aggregates, and the sequence lengths and precise regions involved are different among the diseases. These unique assembled tau cores may be used to classify and diagnose disease strains. Based on these results, we propose a new clinicopathological classification of tauopathies based on the biochemical properties of tau.

Recent studies have shown that a large hexanucleotide expansion in C9ORF72 is the most common cause of inherited Frontotemporal Lobar Degeneration (FTLD) and Motor Neuron Disease (MND).1 In pathological terms, expansion carriers show a distinctive molecular signature within the dentate gyrus granule cells and CA4 pyramidal cells of the hippocampus and granule cells of the cerebellum characterised by TDP-43-negative, but p62-positive, neuronal cytoplasmic inclusions (NCI).2 Such inclusions contain dipeptide repeat proteins (DPR)2 ,3 generated through non-ATG initiated translation of the expanded region of the gene.4 ,5 On immunohistochemistry, an equivalent pattern of immunostaining is observed employing either antibodies to p62 or DPR, and that p62 immunostaining is an effective tool for identification of pathology associated with the presence of hexanucleotide expansions in C9ORF72 .2 ,3 In clinical terms, psychosis is one of the major clinical traits in patients with FTLD and/or …

BACKGROUND AND OBJECTIVE:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by a CAG/polyglutamine repeat expansion, which is associated with a dysregulation of histone function and an impairment of protein transcription. Histone deacetylase (HDAC) inhibitors, such as vorinostat (SAHA), have shown promise as therapeutic agents. However, there have been few studies on the expression of HDACs and acetylated core histones (AcHs) in either normal animals or humans, or in HD patients or HD animal models. Therefore, we investigated the expression of HDACs and AcHs in HD brain by immunohistochemistry, and have compared findings with elderly control subjects and patients with frontotemporal lobar degeneration (FTLD) to determine whether any observed changes were specific for HD. RESULTS AND CONCLUSION:we show specific and significant losses of AcH2A, AcH2B, AcH3 and AcH4 expression from cells in the caudate nucleus and Purkinje cells of the cerebellum in HD compared to patients with FTLD and control subjects, while the level of HDAC 5 was increased in these cells.