Faculty Bibliography

In the USA, between w250,000 e 400,000 individuals have Down syn-drome, and nearly all of them will develop Alzheimer's disease pathology starting in their 30s. By age 70, 50-70% will have dementia. There are numerous pathogenic and mechanistic links between the two disorders. Individuals with DS comprise a potential ideal population for AD clinical trials. The presence of AD pathology in DS has led to greater collaborative research toward the parallel goals of providing effective treatment for individuals with DS and AD, as well as, expediting AD drug development. Similarities and differences between DS and AD will be reviewed. Examples of immunomodulatory and other therapeutic strategies that may benefit both DS and AD will be presented. Over-dosage of the amyloid precursor protein (APP) is believed to be responsible for the high incidence of early-onset AD-like amyloidosis observed in DS patients. APP is cleaved by the sequential proteolytic activity of the B-secretase and the g-secretase complex which is responsible for the formation of amyloid b (Ab). Since activation of the g-secretase complex is the required final step for the formation of Ab, there has been a tremendous effort to develop drugs that block this complex activity as a disease-modifying therapeutic approach for lowering Ab levels. The g-secretase activating protein (GSAP) is a newly recognized protein derived from a larger precursor molecule via a caspase-3-dependent proteolytic cleavage, which by directly interacting with key components of the g-secretase complex acts as a rate-limiting step in Ab formation. Evidence suggests that GSAP is increased in post-mortem brain tissues of AD patients, and its inhibition leads to reduction of AD pathology in transgenic mouse models. Our recent evidence shows that in health control DS brains there is a significant elevation of GSAP protein and mRNA. Targeting of g-secretase as an AD therapy is problematic as it has multiple substrates including Notch. GSAP interacts with g-secretase to enhance Ab production, without affecting Notch. Pharmacological targeting of GSAP is a potentially important therapeutic approach for both DS and AD pathology

Because of an extra copy of the Abeta precursor protein gene on chromosome 21, Down syndrome (DS) individuals develop high levels of Abeta peptides and Alzheimer disease-like brain amyloidosis early in life. Here we show that the gamma-secretase activating protein (GSAP), a key enzyme in amyloidogenesis, is increased in DS brains and specifically regulated at the transcriptional level by GATA1 transcription factor. The discovery of this novel pathway has translational implications for DS, because pharmacological inhibition of GSAP is an attractive and viable Abeta-lowering therapeutic strategy for this disorder. ANN NEUROL 2016;79:138-143.

Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

Alzheimer's disease (AD) is the most common form of dementia worldwide. It is characterized by an imbalance between the production and clearance of amyloid beta (Abeta) and tau proteins. In AD these normal proteins accumulate, leading to aggregation and a conformational change forming oligomeric and fibrillary species with a high beta-sheet content. Active and passive immunotherapeutic approaches result in dramatic reduction of Abeta pathology in AD animal models. However, there is much more limited evidence in human studies of significant clinical benefits from these strategies and it is becoming apparent that they may only be effective very early in AD. Vaccination targeting only tau pathology has shown benefits in some mouse studies but human studies are limited. Greater therapeutic efficacy for the next generation of vaccine approaches will likely benefit from specifically targeting the most toxic species of Abeta and tau, ideally simultaneously.

BACKGROUND: Peripheral surgical trauma may incite neuroinflammation that leads to neuronal dysfunction associated with both depression and cognitive deficits. In a previous study, we found that adult mice developed neuroinflammation and short-term working memory dysfunction in a delayed, transient manner after splenectomy that was ameliorated by the cyclooxygenase-2 inhibitor meloxicam. We tested the hypothesis that splenectomy in mice would also cause anhedonia, the diminished response to pleasure or rewarding stimuli that is a hallmark of depression, and that treatment with meloxicam would be ameliorative. METHODS: After Institutional Animal Care and Use Committee approval, Swiss-Webster mice underwent sucrose preference training before being randomized into groups on day 0, when they had either splenectomy and anesthesia or anesthesia alone. Within each group, half were randomized to receive intraperitoneal saline at 24 hours, while the other half received intraperitoneal meloxicam at 24 hours. Sucrose preference ratios were determined on days 1, 5, 9, and 14. Additional mice were randomized into groups for brain histochemistry. Specimens were stained for glial fibrillary acidic protein (GFAP), a marker of astrocytes, and CD45, a protein tyrosine phosphatase that identifies microglial activation. RESULTS: On day 5, mice receiving splenectomy and saline demonstrated diminished sucrose preference, which was not seen in mice receiving splenectomy and meloxicam. Semiquantitative analysis of histological slides taken from splenectomized mice treated with meloxicam revealed reduced microglial-based neuroinflammation and reactive astrocytosis compared to mice receiving saline. CONCLUSION: Splenectomy in mice is associated with neuroinflammation and anhedonia, as evidenced by reactive microgliosis, astrocytosis, and behavioral changes. Postsurgical treatment with meloxicam attenuates both neuroinflammation and anhedonia. These findings suggest that cyclooxygenase-2-dependent mechanisms may play a role in the development of postoperative mood disorders, possibly via modulation of peripheral effects on neuroinflammation.

Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.

Aggregation of amyloid beta-peptide (Abeta) is implicated in the pathology of Alzheimer's disease (AD), with the soluble, Abeta oligomeric species thought to be the critical pathological species. Identification and characterization of intermediate species formed during the aggregation process is crucial to the understanding of the mechanisms by which oligomeric species mediate neuronal toxicity and following disease progression. Probing these species proved to be extremely challenging, as evident by the lack of reliable sensors, due to their heterogeneous and transient nature. We describe here an oligomer-specific fluorescent chemical probe, BoDipy-Oligomer (BD-Oligo), developed through the use of the diversity-oriented fluorescent library approach (DOFLA) and high-content, imaging-based screening. This probe enables dynamic oligomer monitoring during fibrillogenesis in vitro and shows in vivo Abeta oligomers staining possibility in the AD mice model.