Faculty Bibliography

Background: We have previously demonstrated that anti-beta-sheet conformational monoclonal antibodies (mAbs) recognize pathological oligomeric forms of Abeta and Tau in tissue samples of human Alzheimer's Disease (AD) brains and in AD mouse models (Goni et al 2015, Alzheimer & Dementia pp 845-6). We have now tested one of our mAbs in aged 3xTg AD animals with extensive preexisting Abeta and Tau related pathology with weekly injections of the TABP1 mAb. Methods: Two groups of 16 months old 3xTg AD animals were inoculated i.p. biweekly for three weeks and weekly thereafter for 5 weeks with either 100 mug of TABP1 in 100 muL of sterile saline or with 100 muL of vehicle alone. Radial Arm Maze behavioral analysis was performed after the treatment, followed by sacrifice and harvesting of the brains for immuno-histochemical and biochemical analyses. Results: No adverse reactions were demonstrated during the treatment. The TABP1 infused animals showed significant cognitive rescue compared to the controls. No significant differences were noted with the immunohistochemical quantitation of amyloid plaques or tau pathology; although there was a trend for reduced deposition in the infused animals. However, there was a significant decrease of the soluble and oligomeric Abeta (mainly Abeta1-42) and pathological Tau in the infused animals versus the controls. Conclusions: Anti-conformational monoclonal antibodies infused i.p. can ameliorate behavioral deficits in AD model mice. The mechanism is likely related to reductions of the levels of soluble oligomeric forms of Abeta and Tau; these species have been most closely linked to the cognitive deficits in AD patients. The results are encouraging for the further testing of humanized versions of these mAbs in clinical trials

Background: The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SP) and neurofibrillary tangles (NFTs). Passive immunization with anti-Abeta antibodies is a promising therapeutic approach for AD with several on-going clinical trials; however, toxicity with amyloid related imaging abnormalities (ARIA) is problematic in many of these trails. This toxicity is in part related to the effector function of the antibodies used. Recently, an affibody molecule that lacks effector function, but binds to monomeric Abeta peptides, with aggregation inhibition capacity, was generated and tested in AD model transgenic fruit flies, demonstrating abolition of Abeta related neurotoxic effects and restoration of their life span. Here we assessed the efficacy of passive immunization with the affibody in a mouse model of AD. Methods: APP/ PS1 transgenic AD model mice were injected intraperitoneally twice a week with the Abeta-binding ZSYM73-ABD Affibody molecule from the age of 6 months (at a point where the mice already have amyloid deposition). Control mice received a non-Abeta binding affibody. Their behavior was assessed at 9 months of age and brain tissue subsequently was harvested for analysis of treatment efficacy. Results: The treated (Abeta-binding ZSYM73-ABD) mice didn't show a significant difference from controls on locomotor testing. ZSYM73- ABD treated-mice performed the same as wild-type mice. The amyloid burden of in treated animals was reduced by 49 % in the cortex and 50% in the hippocampus. There was no significant difference in astrogliosis or microhemorrhages between treated and control mice. Conclusions: These results indicate that passive immunization with an Affibody molecule can significantly decrease the amyloid burden and improve cognitive function in a transgenic mouse model of AD

Background: It is now accepted that mitochondrial dysfunction is a key early event in the progression of neuronal and vascular degeneration in Alzheimer's disease (AD) and that therapies aimed at preventing mitochondrial failure may represent promising new strategies in the pursue of a cure for this devastating disease. Carbonic anhydrases (CAs) are a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons (or vice versa), maintaining acid-base balance in blood and other tissues. CA isoforms are present in the mitochondria. CA inhibitors (CAIs), such as metazolamide (MTZ) and acetazolamide (ATZ) are clinically used for glaucoma, epilepsy (rarely), and high altitude sickness. Methods: We analyzed the effects of two main CAIs used in clinical settings (MTZ and ATZ) on the mechanism of mitochondrial damage and neurovascular degeneration induced by amyloid beta (Abeta), using cerebral vascular and neural cells as well as the TgSwDI (Swedish- Dutch-Iowa) transgenic mouse model of cerebral amyloidosis. Results: Both CAIs consistently prevented specific pathways of mitochondrial dysfunction induced by Abeta in cerebral microvascular endothelial, neuronal and glial cells, without affecting ATP production, pH, and Calcium flux. Increase of hydrogen peroxide, loss of mitochondrial membrane potential, release of Cytochrome C, caspase activation, and apoptotic cell death were inhibited by CAIs. ATZ was effective at concentrations lower than MTZ. Both drugs, given with diet, were able to ameliorate behavioral paradigms in relatively young TgSwDI mice. Conclusions: CAIs might represent a potentially successful strategy to prevent early mitochondrial dysfunction and neurovascular loss in AD. Further studies in animal models and clinical settings are needed to confirm our hypothesis

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

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.

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.