Publications

Review the following selected publications, or scroll to the bottom for links to publications by our leading investigators.

Pehar M, Jonas MC, Hare TM, Puglielli L. SLC33A1/AT-1 protein regulates the induction of autophagy downstream of IRE1/XBP1 pathway. J Biol Chem, 2012 Aug 24;287(35):29921-30. PMCID: PMC3436137.

One of the main functions of the unfolded protein response is to ensure disposal of large protein aggregates that accumulate in the lumen of the endoplasmic reticulum (ER) whereas avoiding, at least under nonlethal levels of ER stress, cell death. When tightly controlled, autophagy-dependent ER-associated degradation (ERAD(II)) allows the cell to recover from the transient accumulation of protein aggregates; however, when unchecked, it can be detrimental and cause autophagic cell death/type 2 cell death. Findings for this important paper revealed that IRE1/XBP1 controls the induction of autophagy/ERAD(II) during the unfolded protein response by activating the ER membrane transporter SLC33A1/AT-1, which ensures continuous supply of acetyl-CoA into the lumen of the ER. Failure to induce AT-1 leads to widespread autophagic cell death.

 

Willette AA, Xu G, Johnson SC, Birdsill AC, Jonatis EM, Sager MA, Hermann BP, La Rue A, Asthana S, Bendlin BB. Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care, 36(2):443-449, 2013 Feb. PMCID: PMC3554303.

There is emerging evidence that insulin resistance affects several important cognitive functions of the brain and increases risk for Alzheimer’s disease (AD). The key findings of this paper suggested that insulin resistance in asymptomatic middle-aged adults is associated with progressive atrophy in areas of the brain commonly affected by AD. Additionally, insulin resistance affected episodic memory by reducing gray matter volume in medial temporal lobe.

 

Okonkwo OC, Xu G, Oh JM, Dowling NM, Carlsson CM, Gallgher CL, Birdsill AC, Palotti M, Wharton W, Hermann BP, LaRue AA, Bendlin BB, Rowley HA, Asthana S, Sager MA, Johnson SC. Cerebral blood flow is diminished in asymptomatic middle-aged adults with maternal history of Alzheimer's disease. Cerebral Cortex. 2012 Dec 12. PMID: 23236200.

Cerebral blood flow (CBF) is a marker of cortical metabolic activity and could be a potential biomarker of preclinical stages of AD. This study examined CBF in patients with AD, Mild Cognitive Impairment (MCI), healthy older controls and those with or without a parental history of AD. As expected, the findings of the study suggested that CBF is reduced in selected areas of the brain in patients with AD and MCI. However, reduced CBF was also found in the hippocampus and parieto-frontal regions of the brain in subjects at risk for AD due to a parental history of the disease.

 

Pehar M, Lehnus M, Karst A, Puglielli L. Proteomic assessment shows that many endoplasmic reticulum (ER)-resident proteins are targeted by N(epsilon)-lysine acetylation in the lumen of the organelle and predicts broad biological impact. J Biol Chem, 2012 Jun 29;287(27):22436-40. PMCID: PMC 3391156.

In addition to the nucleus, cytosol, and mitochondrial lumen, N(ε)-lysine acetylation also occurs in the lumen of the endoplasmic reticulum (ER). However, the impact of such an event on ER functions is still unknown. Studies described in this paper analyzed the "ER acetyl-lysine proteome" by nano-LC-MS/MS and discovered that a large number of ER-resident and -transiting proteins undergo N(ε)-lysine acetylation in the lumen of the organelle. The list of ER-resident proteins includes chaperones and enzymes involved with post-translational modification and folding. Grouping of all acetylated proteins into major functional categories suggests that the ER-based acetylation machinery regulates very diverse biological events. As such, it is predicted to play a fundamental role in human physiology as well as human pathology.

 

Bendlin BB, Carlsson CM, Johnson SC, Zetterberg H, Blennow K, Willette AA, Okonkwo OC, Sodhi A, Ries ML, Birdsill AC, Alexander AL, Rowley HA, Puglielli L, Asthana S, Sager MA. CSF T-Tau/Aβ42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease. PLoS One 2012;7(6):e37720. PMCID: PMC 3368882

Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. This study examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. The findings indicated that T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure, notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.

 

Ding Y, Ko MH, Pehar M, Kotch F, Peters NR, Luo Y, Salamat SM, Puglielli L. Biochemical inhibition of acetyltranferases ATase1 and ATase 2 activity reduces β-secretase (BACE1) levels and Aβ generation. J Biol Chem, 2012 Mar 9;287(11):8424-33.  PMCID: PMC3318698

This important paper, for the first time, reports that levels of ATase1 and ATase2, two endoplasmic reticulum (ER)-based acetyl-CoA:lysine acetyltransferases, are up-regulated in the brains of patients with Alzheimer’s disease (AD) and expressed in neurons and glial cells. Both ATase 1 and ATase 2 levels closely regulate cellular levels of BACE1, the rate limiting enzyme in the generation of Aβ. Thus inhibition of activity of ATase1 and ATase2 could potentially reduce the levels of Aβ and favorably alter the pathology of AD. This manuscript from Dr. Puglielli’s laboratory also reports identification of novel inhibitors of ATase1 and ATase2, and describes molecular basis of their action.

 

Johnson SC, LaRue A, Hermann BP, Xu G, Koscik RL, Jonaitis EM, Bendlin BB, Hogan KJ, Roses AD, Saunders AM, Lutz MW, Asthana S, Green RC, Sager MA. The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ɛ3/ ɛ3 genotype. Alzheimer’s Dement., 2011 Jul; 7(4): 456-65. PMCID: PMC3143375.

The key finding of this paper is that a genetic polymorphism at TOMM40 523 may provide additional information to APOE in predicting risk for AD. Specifically, findings described in this paper show that a subgroup of asymptomatic at-risk subjects in the WRAP cohort who are APOE3 homozygotes (the most common form of APOE in the general population, and generally considered to be risk-neutral for AD), may be at increased risk due to TOMM40 523 poly-T repeat lengths. Subjects with longer poly-T repeats had less volume in the posterior cingulate, a region well known to be affected early in the course of AD. Whether this gene leads to higher incidence of other brain changes or cognitive and functional decline in the WRAP sample is now being studied.

 

Okonkwo OC, Xu G, Dowling NM, Bendlin BB, LaRue A, Hermann BP, Koscik R, Jonaitis E, Rowley HA, Carlsson CM, Asthana S, Sager MA, Johnson SC. Family history of Alzheimer’s disease predicts hippocampal atrophy in healthy middle-aged adults. Neurology. 2012 May 29; 78(22): 1769-76.  PMCID: PMC3359586.

The major objective of the study described in this paper was to evaluate longitudinal effects of family history (FH) and APOE4 on brain atrophy and cognitive function in adult, asymptomatic children of patients with AD. The study compared neuroimaging and cognitive data at baseline and 4 year follow-up visit on 60 subjects with and 48 without a FH of AD. The major findings indicated that asymptomatic middle-aged adults (mean age 54 years) with a FH of AD exhibited significant atrophy in the posterior hippocampi, in the absence of measurable changes in cognition. These findings provide additional evidence that detectable disease-related neuroanatomic changes occur early in the AD pathological cascade.

 

Carlsson CM, Xu G, Wen Z, Barnet JH, Blazel HM, Chappell RJ, Stein JH, Asthana S, Sager MA, Alsop DC, Rowley HA, Fain SB, Johnson SC. Effects of atorvastatin on cerebral blood flow in middle-aged adults at risk for Alzheimer’s disease: A pilot study. Curr Alzheimer’s Res. 2012 Oct; 9(8):990-7. PMCID: PMC3576818.

There is converging evidence that elevated levels of cholesterol in midlife leads to cerebrovascular dysfunction and likely increases risk for AD. This study examined potential efficacy of atorvastatin, a statin drug, on cerebral blood flow (CBF), as measured by ASL MRI, and vascular reactivity in middle-aged adult children of patients with AD. The findings of the study indicated that subjects with low baseline HDL-cholesterol, higher global vascular risk and greater endothelial dysfunction, had reduced regional CBF in areas of the brain related to memory and learning. Furthermore, compared to placebo, 4 months of therapy with atorvastatin increased CBF in bilateral hippocampi, fusiform gyrus, putamen and insular cortices. Findings of this study suggested that short-term therapy with atorvastatin improved CBF to specific areas of the brain mediating memory; however, it is currently unknown if this improvement is associated with a delay in the onset of AD.

 

Willette AA, Coe CL, Colman RJ, Bendlin BB, Kastman EK, Field AS, Alexander AL, Allison DB, Weindruch RH, Johnson SC. Calorie restriction reduces psychological stress reactivity and its association with brain volume and microstructure in aged rhesus monkeys. Psychoneuroendocrinology. 2012 Jul; 37(7): 903-16. PMCID: PMC3311744.

There is evidence that heightened stress reactivity is associated with hippocampal atrophy, age-related cognitive deficits and increased risk for AD. This association is reportedly mediated through repeated activation of the HPA axis over time. Caloric restriction (CR) may favorably alter activity of the HPA axis. The study included in this paper involved rhesus monkeys subjected to 30% calorie restriction over a period of 13-19 years. Outcomes included behavioral rating in normative and aversive contexts, volumetric MRI and DTI of the brain and urinary levels of cortisol. Major findings indicated that high stress reactivity predicted lower volume and microstructural density in prefrontal cortices, hippocampus and amygdala, areas of the brain involved in emotional processing and modulation. A CR diet reduced stress reactivity and regional associations with neural modalities. High levels of urinary cortisol appear to mediate some of the adverse relationships between stress and neuroimaging findings.

 

Dowling NM, Olson N, Mish T, Kaprakattu P, Gleason C. A model for the design and implementation of a participant recruitment registry for clinical studies of older adults. Clin Trials. 2012 Apr;9(2):204-14. PMCID: PMC 3325341.

This paper describes the creation of a novel patient recruitment registry and a contact management system by Core C staff of the Wisconsin ADRC that is now been used at 3 ADCs throughout the country. The paper describes the process of creating the above database, called REGGIE, including details of structured problem-solving, systems design approach and data elements and major information domains essential for successful recruitment and retention of study participants in a Center. The inclusion of a contact management system to the registry design significantly improved efficiency of communication between the study coordinator and patient and between each coordinator. This proved to be one of the most successful functionalities of REGGIE.

 

Pehar M, O’Riordan KJ, Burns-Cusato M, Andrzejewski ME, del Alcazar CG, Burger C, Scrable H, & Puglielli L. Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death. Aging Cell. 2010 Apr;9(2), 174-90. PMCID: PMC2848983

The results of seminal paper provide support for a novel therapeutic target. Specifically, findings reported in the paper indicate that increased IGF-1R signaling accelerates AD, whereas reduced IGF-1R signaling prevents it, indicating that IGF-1R is a valid target for the development of new drugs that could prevent or treat the loss of memory that accompanies aging and the neurodegeneration that characterizes AD. The results reported here also reveal a previously unknown link between one of the isoforms of the tumor suppressor/longevity assurance gene p53 and cognition. At the mechanistic level, this link seems to require the microtubule-binding protein tau, which is involved in both AD and non-AD forms of dementia. Previous studies have shown that IGF-1R regulates life span in mammals. In addition, genetic variations that cause reduced IGF-1R signaling appear to be beneficial for old age survival in humans. Therefore, this high-impact study offers a mechanistic proof to the above reports and suggests that IGF-1R is a viable target for therapeutic purposes.

 

Hinrichs C, Singh V, Xu G, & Johnson SC. Predictive markers for AD in a multi-modality framework: An analysis of MCI progression in the ADNI population. Neuroimage. 2011 Mar 15;55(2):574-89. PMCID: PMC3035743.

Drs. Singh (computer scientist and biostatistician in Core C) and Johnson (neuropsychologist, Cores B, D and Project 1) are collaborating on a project in which tools were developed for automated classification of data using machine learning paradigms beyond the simple framework of support vector machines. The paper here illustrates a method using ADNI data that is capable of using several inputs including MRI, PET, CSF markers and cognition into a multi-kernel machine learning framework. We showed in the ADNI sample the value of considering multiple clinically relevant pieces of information in a single discriminative algorithm. We are now extending the idea into informing and enriching clinical trials with subjects identified (with the algorithm) that are most likely to decline to AD.

 

Bendlin BB, Ries ML, Canu E, Lazar M, Alexander AL, Carlsson CM, Sager MA, Asthana S, & Johnson SC. White matter is altered with parental family history of Alzheimer’s disease. Alzheimer’s Dement. 2010 Sep; 6(5), 394-403. PMCID: PMC2933285

In this study, we examined parental family history of AD to assess the extent to which it exerts an effect on brain health beyond that of APOE4. We found in this study that parental family history of AD is associated with white matter alterations in AD-relevant brain regions. Furthermore, family history interacted with APOE4, that is, participants with both family history and APOE4 showed the greatest alteration in brain white matter health. The results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset, and furthermore that family history of AD is a potent risk factor in need of increased attention in the study of preclinical AD.

 

Dowling NM, Hermann B, La Rue A, & Sager MA. Latent structure and factorial invariance of a neuropsychological test battery for the study of preclinical Alzheimer’s disease. Neuropsychology. 2010 Nov;24(6), 742-56. PMCID: PMC 3057903

This paper provided results from exploratory and confirmatory factor analyses of cognitive data from the NIA-funded Wisconsin Registry for Alzheimer’s Prevention (WRAP) involving 1,288 asymptomatic middle-aged adults (mean age: 53 years) with (n=942) or without (n=346) a parental history of AD. This five-factor solution demonstrated strong psychometric properties and was invariant across subgroups (i.e., parental history positive v. negative, men v. women, etc.). This factor structure will serve as the basis for cognitive summary scores for use in all subsequent WRAP research. Moreover, it should prove useful for other studies involving early detection of cognitive symptoms in middle aged adults at-risk for AD, such as the ADRC IMPACT cohort.

 

Kastman EK, Willette AA, Coe CL, Bendlin BB, Kosmatka KJ, McLaren DG, Xu G, Canu E, Field AS, Alexander AL, Voytko ML, Beasley TM, Colman RJ, Weindruch RH, & Johnson SC. A calorie-restricted diet decreases brain iron accumulation and preserves motor performance in old rhesus monkeys. J Neuroscience. 2012 Aug 22;32(34): 11897-904. PMCID:PMC3548565.

This landmark paper includes findings from an NIA-funded, 20-year longitudinal study in aged rhesus monkeys demonstrating that caloric restriction (CR) attenuates age-related fine motor slowing. We also found that a well-known marker of aging—iron deposition in the basal ganglia—is also attenuated under a calorie-restricted diet. The brain-related findings from this study have direct relevance to the field of AD research and require additional studies in animal models of AD. Dr. Sterling Johnson, a senior investigator at the Wisconsin ADRC, directed the imaging studies of the brain.

View the latest publications from these leading investigators:

Sanjay Asthana, MD, FRCP (C)

Piero Antuono, MD

Craig Atwood, PhD

Barbara Bendlin, PhD

Cindy Carlsson, MD, MS

Rick Chappell, PhD

N. Maritza Dowling, PhD

Dorothy Farrar-Edwards, PhD

Carey Gleason, PhD, MS

Sterling Johnson, PhD

Ozioma Okonkwo, PhD

Luigi Puglielli, MD, PhD

Mark Sager, MD

M. Shahriar Salamat, MD, PhD