Telomeric alterations in the default mode network during the progression of Alzheimer's disease: Selective vulnerability of the precuneus.

AIMS: Although telomere length (TL) and telomere maintenance proteins (shelterins) are markers of cellular senescence and peripheral blood biomarkers of Alzheimer's disease (AD), little information is available on telomeric alterations during the prodromal stage (MCI) of AD. We investigated TL in the default mode network (DMN), which underlies episodic memory deficits in AD, as well as shelterin protein and mRNA levels in the precuneus (PreC). METHODS: Telomere length was evaluated in DMN hubs and visual cortex using quantitative PCR (qPCR). In the PreC, western blotting and NanoString nCounter expression analyses evaluated shelterin protein and mRNA levels, respectively, in cases with an antemortem clinical diagnosis of no cognitive impairment (NCI), MCI and AD. RESULTS: TL was significantly reduced in the PreC in MCI and AD compared to NCI, but stable in frontal, inferior temporal, posterior cingulate and visual cortex. PreC TL correlated significantly with performance on cognitive tests. NCI cases with high vs low Braak scores displayed significantly shorter TL in posterior cingulate and frontal cortex, which correlated significantly with neuritic and diffuse amyloid-ß plaque counts. Shelterin protein levels (TIN2, TRF1, TRF2 and POT1) declined in MCI and AD compared to NCI. The PreC displayed stable expression of shelterins TERF1, TERF2, POT1, RAP1 and TPP1, while TINF2 mRNA significantly increased in AD compared to NCI. CONCLUSIONS: These findings indicate a selective vulnerability to telomere attrition within different nodes of the DMN in prodromal AD and in aged NCI individuals with high Braak scores highlighting a putative role in the pathogenesis of AD.

Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: A chronic effects of neurotrauma consortium study.

OBJECTIVE: To test the hypothesis that the nucleus basalis of Meynert (nbM), a cholinergic basal forebrain (CBF) cortical projection system, develops neurofibrillary tangles (NFTs) during the progressive pathological stages of chronic traumatic encephalopathy (CTE) in the brain of athletes. METHOD: To characterize NFT pathology, tau-antibodies marking early, intermediate and late stages of NFT development in CBF tissue obtained at autopsy from eighteen former athletes and veterans with a history of repetitive mild traumatic brain injury (TBI) were used. RESULTS: Analysis revealed that cholinergic nbM neurons develop intracellular tau-immunoreactive changes progressively across the pathological stages of CTE. In particular, there was an increase in pre-tangle (phosphorylated pS422) and oligomeric (TOC1 and TNT1) forms of tau in stage IV compared to stage II CTE cases. The nbM neurons also displayed pathologic TDP-43 inclusions and diffuse extracellular and vascular amyloid-ß (Aß) deposits in CTE. A higher percentage of pS422/p75NTR, pS422 and TNT1 labelled neurons were significantly correlated with age at symptom onset, interval between symptom onset and death and age at death. CONCLUSION: The development of NFTs within the cholinergic nbM neurons could contribute to an axonal disconnection in CTE. Further studies are needed to determine the mechanism driving NFT formation in the nbM neurons and its relation to chronic cognitive dysfunction in CTE.

Oligomeric, phosphorylated, and truncated tau and spliceosome pathology within the entorhinal-hippocampal connectome across stages of Alzheimer's disease.

Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the density of posttranslational oligomeric (TOC1 and TNT1), phosphorylated (AT8), and late truncated (TauC3) tau epitopes within the MTL subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Although a significant increase in TOC1, TNT1, and AT8 neuron density occurred in the EC in MCI and AD, subicular, DG granule cell, and CA1 and CA3 densities were only significantly higher in AD. TauC3 counts were not different between connectome regions and clinical groups. SRSF2 intensity in AT8-positive cells decreased significantly in all regions independent of the clinical groups examined. CA1 and subicular AT8, TauC3, and oligomeric densities correlated across clinical groups. EC AT8 counts correlated with CA subfields and subicular and DG values across clinical groups. Oligomeric and AT8 CA1, EC, and subicular density correlated with Braak stage. Decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated tau suggests a dual-hit process in NFT formation within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal-hippocampal connectome.

Social cognition in cervical dystonia.

Background: Whilst traditionally considered a movement disorder, it is now generally accepted that cervical dystonia (CD) presents with additional non-motor symptoms which significantly impact quality of life. Our study primarily aimed to explore social cognition and levels of psychological distress in individuals with CD, in comparison to age- and sex-matched healthy controls. Methods: 20 participants with CD attending a specialist movement disorders clinic were recruited. 20 age and sex matched neurologically healthy controls were recruited in parallel. Participants completed the Hospital Anxiety and Depression Scale, and two novel social cognition tasks: The Cambridge Mindreading Face-Voice Battery (CAFMB) and the Edinburgh Social Cognition Test (ESCoT). Results: Participants with CD exhibited poorer complex emotion recognition abilities for visual and auditory stimuli, compared to controls on the CAFMB task. Participants with CD did not differ significantly from controls on performance on cognitive or affective Theory of Mind tasks, or interpersonal or intrapersonal understanding of social norms, as measured by the ESCoT. The proportion of depressive symptoms was significantly higher for participants with CD than controls. 40% of participants with CD reported clinically elevated depressive symptoms, and 60% reported clinically elevated anxiety. Poorer understanding of emotional facial expressions was associated with higher levels of depression in the CD group. Conclusions: Significant between-group differences between participants with CD and controls suggests socio-cognitive dysfunction is an important aspect of the non-motor syndrome of CD. Findings highlight the need for assessment of and intervention for both social cognitive difficulties and psychological distress in individuals with CD.

Remote Ischemic Post-Conditioning Therapy is Protective in Mouse Model of Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) is characterized by visual dysfunction after indirect or direct injury to the optic nerve following blunt head trauma. TON is associated with increased oxidative stress and inflammation resulting in retinal ganglion cell (RGC) death. Remote ischemic post-conditioning (RIC) has been shown to enhance endogenous protective mechanisms in diverse disease models including stroke, vascular cognitive impairment (VCI), retinal injury and optic nerve injury. However, the protective mechanisms underlying the improvement of retinal function and RGC survival after RIC treatment remain unclear. Here, we hypothesized that RIC therapy may be protective following TON by preventing RGC death, oxidative insult and inflammation in the mouse retina. To carry out the study, mice were divided in three different groups (Control, TON and TON + RIC). We harvested retinal tissue 5 days after TON induction for western blotting and histochemical analysis. We observed increased TON-induced retinal cell death compared with controls by cleaved caspase-3 immunohistochemistry. Furthermore, the TON cohort demonstrated increased TUNEL positive cells which were significantly attenuated by RIC. Immunofluorescence data showed that oxidative stress markers dihydroethidium (DHE), NOX-2 and nitrotyrosine expression were elevated in the TON group relative to controls and RIC therapy significantly reduced the expression level of these markers. Next, we found that the proinflammatory cytokine TNF-α was increased and anti-inflammatory IL-10 was decreased in plasma of TON animals, and RIC therapy reversed this expression level. Interestingly, western blotting of retinal tissue showed that RGC marker Brn3a and tight junction proteins (ZO-1 and Occludin), and AMPKα1 expression were downregulated in the TON group compared to controls. However, RIC significantly increased the expression levels of these proteins. Together these data suggest that RIC therapy activates endogenous protective mechanisms which may attenuate TON-induced oxidative stress and inflammation, and improves BRB integrity.

Nerve Growth Factor Pathobiology During the Progression of Alzheimer's Disease.

The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer's disease (AD). Both transcript and protein data indicate that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75NTR-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75NTR death receptor for the treatment of AD.

Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer's Disease.

Although the frontal cortex plays an important role in cognitive function and undergoes neuronal dysfunction in Alzheimer's disease (AD), the factors driving these cellular alterations remain unknown. Recent studies suggest that alterations in epigenetic regulation play a pivotal role in this process in AD. We evaluated frontal cortex histone deacetylase (HDAC) and sirtuin (SIRT) levels in tissue obtained from subjects with a premortem diagnosis of no-cognitive impairment (NCI), mild cognitive impairment (MCI), mild to moderate AD (mAD), and severe AD (sAD) using quantitative western blotting. Immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD compared to NCI. HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in MCI and mAD, but not in sAD compared to NCI. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to NCI. HDAC1 levels negatively correlated with perceptual speed, while SIRT1 positively correlated with perceptual speed, episodic memory, global cognitive score, and Mini-Mental State Examination. HDAC1 positively, while SIRT1 negatively correlated with cortical neurofibrillary tangle counts. These findings suggest that dysregulation of epigenetic proteins contribute to neuronal dysfunction and cognitive decline in the early stage of AD.

Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain.

Central cholinergic structures within the brain of the even-toed hoofed Goettingen miniature domestic pig (Sus scrofa domesticus) were evaluated by immunohistochemical visualization of choline acetyltransferase (ChAT) and the low-affinity neurotrophin receptor, p75NTR . ChAT-immunoreactive (-ir) perikarya were seen in the olfactory tubercle, striatum, medial septal nucleus, vertical and horizontal limbs of the diagonal band of Broca, and the nucleus basalis of Meynert, medial habenular nucleus, zona incerta, neurosecretory arcuate nucleus, cranial motor nuclei III and IV, Edinger-Westphal nucleus, parabigeminal nucleus, pedunculopontine nucleus, and laterodorsal tegmental nucleus. Cholinergic ChAT-ir neurons were also found within transitional cortical areas (insular, cingulate, and piriform cortices) and hippocampus proper. ChAT-ir fibers were seen throughout the dentate gyrus and hippocampus, in the mediodorsal, laterodorsal, anteroventral, and parateanial thalamic nuclei, the fasciculus retroflexus of Meynert, basolateral and basomedial amygdaloid nuclei, anterior pretectal and interpeduncular nuclei, as well as select laminae of the superior colliculus. Double immunofluorescence demonstrated that virtually all ChAT-ir basal forebrain neurons were also p75NTR -positive. The present findings indicate that the central cholinergic system in the miniature pig is similar to other mammalian species. Therefore, the miniature pig may be an appropriate animal model for preclinical studies of neurodegenerative diseases where the cholinergic system is compromised. J. Comp. Neurol. 525:553-573, 2017. © 2016 Wiley Periodicals, Inc.