Simon D'Alton

Wild-Type Human TDP-43 Expression Causes TDP-43 Phosphorylation, Mitochondrial Aggregation, Motor Deficits, and Early Mortality in Transgenic Mice

Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.

Changing perspectives on Alzheimer's disease: thinking outside the amyloid box.

The past two decades have seen an explosion in funding and research for Alzheimers disease (AD), which has resulted in a wealth of data exploring the potential underlying processes, particularly with regard to amyloid-β (Aβ). However, to date, therapies based on this knowledge have not been forthcoming. In seeking an explanation for our current pharmacological failures, it has become clear that amyloid is only one part of a multi-factorial disease process incorporating a wealth of deleterious factors. Additionally, there is strong evidence that the initial production of Aβ is part of the evolutionarily conserved stress response, triggered by a host of upstream factors highly altered in aging. Taken together, these observations place Aβ in a drastically different context, with toxicity occurring secondarily to upstream deleterious factors and rendering current therapeutic strategies oversimplified. This re-conceptualization necessitates a paradigm shift in our scientific and social response to AD, placing a greater emphasis on upstream interventions and public health awareness of the measures that can be taken by most individuals to reduce the risk of AD. With the increasing prevalence of AD and the realization that disease-modifying drugs may not be available in the near future, it is the responsibility of science to better communicate the worth of preventative healthcare measures to the public.

Describing the dying days of "alzheimer's disease"

There is no doubt that individuals, families, communities, and governments face an enormous challenge in the growing number of persons with dementia in our societies. Accompanying this demographic boom is an opportunity to examine the way we think about the vast, miscellaneous category we currently call “Alzheimer’s disease”, (AD), which has just eclipsed its 100th year in the medical lexicon. The current dominant molecular paradigm has been advantageous in raising awareness of senile dementia, generating funding, and stimulating research and discourse. However, after the failure of over twenty anti-amyloid drugs in the past decade, the amyloid cascade hypothesis is now dying and losing its fearproducing grip on the public. In light of these failures, calls for more money for failed approaches appear to meet the Einsteinium definition of insanity by trying to solve a problem through the recapitulation of

Understanding the role of progranulin in Alzheimer's disease

Alzheimers disease is characterized by severe cognitive decline and brain amyloid plaques. A new study in mouse models that develop features of Alzheimers disease indicates that progranulin may have a role in clearing these plaques.

Heterogeneity of Matrin 3 in the developing and aging murine central nervous system

Mutations in the MATR3 gene encoding the nucleotide binding protein Matrin 3 have recently been identified as causing a subset of familial amyotrophic lateral sclerosis (fALS) and more rarely causing distal myopathy. Translating the identification of MATR3 mutations into an understanding of disease pathogenesis and the creation of mouse models requires a complete understanding of normal Matrin 3 levels and distribution in vivo. Consequently, we examined the levels of murine Matrin 3 in body tissues and regions of the central nervous system (CNS). We observed a significant degree of variability in Matrin 3 protein levels among different tissues of adult animals, with the highest levels found in reproductive organs and the lowest in muscle. Within the adult CNS, Matrin 3 levels were lowest in spinal cord. Further, we found that Matrin 3 declines significantly in CNS through early development and young adulthood before stabilizing. As previously reported, antibodies to Matrin 3 primarily stain nuclei, but the intensity of staining was not uniform in all nuclei. The low levels of Matrin 3 in spinal cord and muscle could mean that that these tissues are particularly vulnerable to alterations in Matrin 3 function. Our study is the first to characterize endogenous Matrin 3 in rodents across the lifespan, providing the groundwork for deciphering disease mechanisms and developing mouse models of MATR3‐linked ALS. J. Comp. Neurol. 524:2740–2752, 2016.

Adapting to dementia in society: a challenge for our lifetimes and a charge for public health.

For the last several decades, Alzheimers disease (AD) has been widely regarded as a late life event, but is now being redefined as a chronic condition that develops over decades. Concurrently, a preponderance of evidence emerging from basic and clinical research in diverse fields such as cardiovascular, endocrine, and mental health has suggested that the environmental component of clinical AD is not only multifactorial in populations and in individuals, but is also modifiable across the life-course, from conception until death. Re-conceptualizing the environmental component of AD to account for these observations necessitates an approach to brain health that eschews singular, short- and medium-term methodology and instead reflects long-term complexity. Such thinking is consistent with the ecological models of public health, which emphasize the development of community infrastructure that can foster population and individual health over the life-course by minimizing risk through multifaceted, systemic approaches.

Review of “You're Looking At Me Like I Live Here And I Don't”

Artistic depictions of Alzheimer’s disease (AD) in mainstream culture have long tended toward the predictable and melodramatic. Tropes of loss, decline, and sadness predominate, with AD often personified as a ravaging disease that steals the self. However, thanks to the ascendancy of the person-centered care and culture change movements over the past decade, there has been a shift away from the hoary disease narrative and an increasing focus on the nuanced human aspects of the illness. You’re Looking At Me Like I Live Here And I Don’t—billed as the first documentary filmed exclusively in an Alzheimer’s care unit and told from the perspective of a person with AD—is part of this trend. Set at a residential facility in Danville, California, the film follows Lee Gorewitz, a 70-something woman with significant memory loss and aphasia, as she goes about her daily life in a locked unit over a 6-month period. Director Scott Kirschenbaum and his team remain conspicuously absent from the film, relying exclusively on the actions of Lee and her fellow residents to push the story forward. There are no “cut-in” interviews with nursing staff or family members, no authoritative “non-demented” narration to provide context or interpretation. Like Lee, the viewer is trapped in the locked unit and subjected to fleeting, episodic, and disorienting moments that are unanchored in time or meaningful context.

Lessons learned from emerging mouse models of TDP-43 proteinopathy

not available. S5-02-04 RELATIONSHIPS OF CEREBROVASCULAR ATHEROSCLEROSIS WITH AMYLOID, TAU, a-SYNUCLEIN AND TDP-43 PATHOLOGIES IN NEURODEGENERATIVE DISEASE DEMENTIAS Mark Yarchoan, Sharon X. Xie, Mitchel A. Kling, Juan B. Toledo, David A. Wolk, Edward B. Lee, Vivianna M. Van Deerlin, M.Y. Lee Virginia, John Q. Trojanowski, Steven E. Arnold, University of Pennsylvania, Philadelphia, Pennsylvania, United States. Background: Accumulating epidemiological data link atherosclerosis with Alzheimer’s disease (AD) and possibly other neurodegenerative diseases. Risk factors that are common among these include age, APOE-ε4 polymorphism, smoking, inflammation, obesity and the metabolic syndrome. Yet the nature and specificity of atherosclerotic vascular contributions to AD or other neurodegenerative diseases remain unclear. To address this, we investigated the frequency and grades of atherosclerotic plaques in the circle of Willis in AD and multiple other neurodegenerative diseases and we correlated severity ratings with the molecular pathological lesions of these diseases. Methods: Semi-quantitative data from gross and microscopic neuropathological exams in 1000 cases from the University of Pennsylvania’s Alzheimer’s Disease Center and Center for Neurodegenerative Disease Research were analyzed, including 410 with a primary diagnosis of AD, 230 with synucleinopathies (Parkinson’s disease with and without dementia, dementia with Lewy bodies, multiple system atrophies), 157 with TDP-43 proteinopathies (frontotemporal dementias, amyotrophic lateral sclerosis), 144 with tauopathies (Pick’s disease, progressive supranclear palsy, corticobasal degeneration and others), and 59 with normal aging. ANOVA, logistic and linear regression models assessed the relationships of circle of Willis atherosclerosis ratings with diagnoses and histological ratings of neurodegenerative disease lesions labeled with thioflavin-S and antibodies directed at PHFtau, a-synuclein and TDP43 in multiple cortical and subcortical brain regions. Results: Over 77% of AD subjects had grossly apparent circle of Willis atherosclerosis, a percentage that was significantly higher than normal (47%), or other neurodegenerative diseases (43-67%). Age and sex adjusted atherosclerosis ratings were highly correlated with neuritic plaque (P <0.0001) and PHFtau neurofibrillary tangle (P <0.0001) ratings in the whole sample and within individual groups. We found no such associations between atherosclerosis ratings and a-synuclein or TDP-43 lesion ratings either in the whole sample or in individual disease categories. Conclusions: These results provide further confirmation that atherosclerotic vascular disease in the circle of Willis and AD are interrelated. We also find that this association is relatively specific to AD and is not observed with other major neurodegenerative diseases or disease lesions. Our findings are consistent with a hypothesis that common etiologic or reciprocally synergistic pathophysiological mechanisms promote both atherosclerotic vascular pathology and plaque and tangle pathology. Featured Research Sessions: F5-01: Applications of Electrophysiological Methods in the Field of Alzheimer’s Disease (PIA: Electrophysiology) P725

Neurons during early development are highly vulnerable to TDP-43 dysregulation

P3-006 NEURONS DURING EARLY DEVELOPMENTARE HIGHLY VULNERABLE TO TDP-43 DYSREGULATION Ashley Cannon, Baoli Yang, Joshua Knight, Mackenzie Farnham, Yongjie Zhang, Charles Wuertzer, Simon D’Alton, John Howard, Wenlang Lin, Brittany Scott, Michael Jurasic, Xin Yu, Rachel Bailey, Dennis Dickson, Leonard Petrucelli, Jada Lewis, Mayo Clinic, Jacksonville, Florida, United States; University of Iowa, Iowa City, Iowa, United States; University of Florida, Gainesville, Florida, United States.