Alexander J. Ehrenberg

Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery.

Alzheimers disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstems locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]).

Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's Disease

Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht‐NCI) are the best protein correlate of clinical decline in Alzheimers disease (AD). Qualitative evidence identifies ht‐NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht‐NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages.

Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study

The brainstem nuclei of the reticular formation (RF) are critical for regulating homeostasis, behavior, and cognition. RF degenerates in tauopathies including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Although the burden of phopho-tau inclusion is high across these diseases, suggesting a similar vulnerability pattern, a distinct RF-associated clinical phenotype in these diseases indicates the opposite. To compare patterns of RF selective vulnerability to tauopathies, we analyzed 5 RF nuclei in tissue from 14 AD, 14 CBD, 10 PSP, and 3 control cases. Multidimensional quantitative analysis unraveled discernable differences on how these nuclei are vulnerable to AD, CBD, and PSP. For instance, PSP and CBD accrued more tau inclusions than AD in locus coeruleus, suggesting a lower vulnerability to AD. However, locus coeruleus neuronal loss in AD was so extreme that few neurons remained to develop aggregates. Likewise, tau burden in gigantocellular nucleus was low in AD and high in PSP, but few GABAergic neurons were present in AD. This challenges the hypothesis that gigantocellular nucleus neuronal loss underlies REM behavioral disorders because REM behavioral disorders rarely manifests in AD. This study provides foundation for characterizing the clinical consequences of RF degeneration in tauopathies and guiding customized treatment.

APOPTOSIS AND AUTOPHAGY CHANGES CORRELATE WITH ALZHEIMER'S DISEASE PROGRESSION IN HUMANS: A STEREOLOGICAL POSTMORTEM STUDY

in the limbic system and progressively spreads into primary processing and sensory regions such as the primary visual cortex and the retina. For the first time, here we assess the propagation of Ab42 peptide-mediated amyloidogenesis and pro-inflammatory gene expression (at the level of miRNA, mRNA and protein) in the neocortical-thalamic-retinal visual pathway of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum (sulfate). Methods:5xFAD Tg-AD murine models, RNA sequencing, GeneChip (microRNA and mRNA), RT-PCR, LED-Northern, Western, ELISA and bioinformatics analysis. Results:The three most significant findings were (i) in aluminum-supplemented animals, markers for inflammatory neuropathology appeared in both the brain and the retina as evidenced by an evolving presence of Ab42 peptides; (ii) increases in Ab42 peptide abundance in these animals were accompanied by the up-regulation of several pro-inflammatory markers including cyclooxygenase-2 (COX-2) and C-reactive protein (CRP); and (iii) that as similarly reported in other Tg-AD murine models, there was a significantly accelerated development of Ab42-mediated inflammatory neuropathology in 5xFAD Tg-AD mice fed aluminum. Conclusions: Taken together the results indicate that in the 5xFAD Tg-ADmodel aluminum not only enhances an Ab42-mediated inflammatory neurodegeneration in the brain but also significantly induces AD-type neuropathology in anatomically-linked primary sensory areas that involve the acquisition and processing of visual signals.

Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans

Clarifying the mechanisms connecting neurofibrillary tangle (NFT) neurotoxicity to neuronal dysfunction in humans is likely to be pivotal for developing effective treatments for Alzheimers disease (AD). To model the temporal progression of AD in humans, we used a collection of brains with controls and individuals from each Braak stage to quantitatively investigate the correlation between intraneuronal caspase activation or macroautophagy markers, NFT burden, and neuronal loss, in the dorsal raphe nucleus and locus coeruleus, the earliest vulnerable areas to NFT accumulation. We fit linear regressions with each count as outcomes, with Braak score and age as the predictors. In progressive Braak stages, intraneuronal active caspase-6 positivity increases both alone and overlapping with NFTs. Likewise, the proportion of NFT-bearing neurons showing autophagosomes increases. Overall, caspases may be involved in upstream cascades in AD and are associated with higher NFTs. Macroautophagy changes correlate with increasing NFT burden from early AD stages.

Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer’s Disease

Clarifying the relationships between neuropsychiatric symptoms and Alzheimers disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Commentary: Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice

German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany, 2 Institute of Cognitive Neurology and Dementia Research, Otto von Guericke University Magdeburg, Magdeburg, Germany, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States, 4 Institute of Cognitive Neuroscience, University College London, London, United Kingdom, 5 The Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom

REGIONAL NEUROFIBRILLARY TANGLE DISTRIBUTION AS A CONTRIBUTOR TO CLINICAL HETEROGENEITY IN ALZHEIMER’S DISEASE

year) showed a slower rate of cognitive decline compared to the untreated HpSp (-7.1 points/year) and typical cases (-1.6), although not significant (p1⁄40.141 and p1⁄40.245, respectively). Limbic predominant did not show a difference (p1⁄40.901). Conclusions: The findings support the hypothesis that neuropathologic heterogeneity ofAD subtypes extends to the differential involvement of the cholinergic system. Although caution is needed due to the retrospective nature of our study, our findings suggest that cholinergic treatment may have a greater benefit in HpSp subtype of AD.

ACETYLATED TAU DISTRIBUTION IN THE HUMAN HIPPOCAMPUS

utilized for the prevention of memory loss or restoration of lost memories. In our study we investigated how production of new hippocampal neurons changes with age.Methods:C57BL/6J male mice were obtained from The Jackson Laboratory (Bar Harbor, ME). The mouse age ranged from 30 days to 2.5 years. Proliferating cells in themouse brain were labeled by a single intraperitoneal injection of 5-Ethynyl-20-deoxyuridine. Mouse brains were processed, stained for EdU, and coordinate of all proliferating cells were obtained and represented as a point cloud. Results:We found that production of neural precursors decreases 64 fold from the age of 30 days to the age of 2.5 years. Based on our measurements, we calculated that during this time 1,665,965 new precursors are produced in the subgranular zone (SGZ). The SGZ contains presumptive neural stem cells (NSCs). Using the published estimates of the number of such cells in the SGZ, we calculated that each presumptive NSC on average produces only 33 progenies between the age of 2months and 2.5 years. We propose a model that mechanistically explains changes in neurogenesis with age and also discuss possible implications of this new model on the development of new therapies based on the induction of neurogenesis in the SGZ. Conclusions: Our model predicts that only treatments which induce neurogenesis by extending the proliferative potential of NSCs or treatments that replenish the NSC population, based for example on the expansion of NSCs poll by promoting symmetrical NSCs division or by introduction of additional NSCs in the SGZ by somatic-stem conversion, should be used. This study was supported by the Janet and Edward Gilda Charitable Foundation and in part by the Department of Veterans Affairs.

TAU-INDUCED PATHOLOGICAL CHANGES IN THE HUMAN LOCUS COERULEUS DURING ALZHEIMER’S DISEASE PROGRESSION

is modulating frontoparietal network activity and thereby influencing selective attention.We find age-related impairments in these processes that can be alleviated by increasing tonic LC activity with a simple exercise. In addition, diminished connectivity between the LC and frontoparietal network is associated with decreased LC neuromelaninMRI contrast. Thus, our findings not only provide evidence of age-related decline in LC function, but also provide insights into how exercise can enhance cognition in aging.