Philip P. Foster

Exercise-Induced Cognitive Plasticity, Implications for Mild Cognitive Impairment and Alzheimer’s Disease

Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer’s disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The “inward” continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal “outward” continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid β (Aβ) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders.

Klotho Protects Dopaminergic Neuron Oxidant-Induced Degeneration by Modulating ASK1 and p38 MAPK Signaling Pathways.

Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal levels of 8-hydroxy-2-deoxyguanosine, albeit this anti-oxidant defense mechanism has not been locally investigated in the brain. Here, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK pathway regulates stress levels in the brain of these mice and showed that: 1) the ratio of free ASK1 to thioredoxin (Trx)-bound ASK1 is relatively lower in the transgenic brain whereas the reverse is true for the Klotho knockout mice; 2) the reduced p38 activation level in the transgene corresponds to higher level of ASK1-bound Trx, while the KO mice showed elevated p38 activation and lower level of–bound Trx; and 3) that 14-3-3ζ is hyper phosphorylated (Ser-58) in the transgene which correlated with increased monomer forms. In addition, we evaluated the in vivo robustness of the protection by challenging the brains of Klotho transgenic mice with a neurotoxin, MPTP and analyzed for residual neuron numbers and integrity in the substantia nigra pars compacta. Our results show that Klotho overexpression significantly protects dopaminergic neurons against oxidative damage, partly by modulating p38 MAPK activation level. Our data highlight the importance of ASK1/p38 MAPK pathway in the brain and identify Klotho as a possible anti-oxidant effector.

How does dancing promote brain reconditioning in the elderly

1 The Brown Foundation, Department of NanoMedicine and Biomedical Engineering, Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, USA 2 Division of Pulmonary, Sleep Medicine, and Critical Care, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA *Correspondence: ppfoster@utmb.edu

Klotho Regulates 14-3-3ζ Monomerization and Binding to the ASK1 Signaling Complex in Response to Oxidative Stress

The reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1) signaling complex is a key regulator of p38 MAPK activity, a major modulator of stress-associated with aging disorders. We recently reported that the ratio of free ASK1 to the complex-bound ASK1 is significantly decreased in Klotho-responsive manner and that Klotho-deficient tissues have elevated levels of free ASK1 which coincides with increased oxidative stress. Here, we tested the hypothesis that: 1) covalent interactions exist among three identified proteins constituting the ASK1 signaling complex; 2) in normal unstressed cells the ASK1, 14-3-3ζ and thioredoxin (Trx) proteins simultaneously engage in a tripartite complex formation; 3) Klotho’s stabilizing effect on the complex relied solely on 14-3-3ζ expression and its apparent phosphorylation and dimerization changes. To verify the hypothesis, we performed 14-3-3ζ siRNA knock-down experiments in conjunction with cell-based assays to measure ASK1-client protein interactions in the presence and absence of Klotho, and with or without an oxidant such as rotenone. Our results show that Klotho activity induces posttranslational modifications in the complex targeting 14-3-3ζ monomer/dimer changes to effectively protect against ASK1 oxidation and dissociation. This is the first observation implicating all three proteins constituting the ASK1 signaling complex in close proximity.

Effects of hyperbaric oxygen preconditioning on cardiac stress markers after simulated diving

Hyperbaric oxygen preconditioning (HBO‐PC) can protect the heart from injury during subsequent ischemia. The presence of high loads of venous gas emboli (VGE) induced by a rapid ambient pressure reduction on ascent from diving may cause ischemia and acute heart failure. The aim of this study was to investigate the effect of diving‐induced VGE formation on cardiac stress marker levels and the cardioprotective effect of HBO‐PC. To induce high loads of VGE, 63 female Sprague–Dawley rats were subjected to a rapid ambient pressure reduction from a simulated saturation dive (50 min at 709 kPa) in a pressure chamber. VGE loads were measured for 60 min in anesthetized animals by the use of ultrasonography. The animals were divided into five groups. Three groups were exposed to either diving or to HBO‐PC (100% oxygen, 38 min at 303 kPa) with a 45 or 180 min interval between HBO‐PC and diving. Two additional groups were used as baseline controls for the measurements; one group was exposed to equal handling except for HBO‐PC and diving, and the other group was completely unexposed. Diving caused high loads of VGE, as well as elevated levels of the cardiac stress markers, cardiac troponin T (cTnT), natriuretic peptide precursor B (Nppb), and αB‐crystallin, in blood and cardiac tissue. There were strong positive correlations between VGE loads and stress marker levels after diving, and HBO‐PC appeared to have a cardioprotective effect, as indicated by the lower levels of stress marker expression after diving‐induced VGE formation.

The "brain-skin connection" in protein misfolding and amyloid deposits: embryological, pathophysiological, and therapeutic common grounds?

A brief history of amyloidosis goes back to autopsies of the seventeenth century reporting a waxing substance (Cordier, 2008). Later, in the middle of the nineteenth century, Rudolph Virchow described an “amyloid” (starch, amulon, Greek, amylum, Latin) degeneration and infiltration of the lungs within alveoli and small vessels in a patient who presented with systemic amyloidosis (heart, lungs, liver, and kidneys; Cordier, 2008). What amyloid-related diseases share is a common molecular ternary structure which involves abnormal aggregation of numerous widespread copies of the same protein into well-ordered filamentous β-sheet rich structures (Friedman, 2011) known as amyloid fibrils of 10–12 nm diameters (Plante-Bordeneuve and Said, 2011). This abnormal accumulation of amyloid oligomers, protofibrils, or fibrils is considered to be one of the major contributor to neurodegeneration and the hallmark of Alzheimers (AD) and Parkinsons diseases (Arora et al., 2004). A primary cause underlying these accumulations is the folding of polypeptide chains to specific three-dimensional proteins in abnormal ways (Selkoe, 2003). The progressive misfolding of specific proteins into aggregation may lead to cell alteration or death. Aggregated forms share many characteristics. One of them is that amyloid deposits show specific optical behavior such as birefringence on binding dyes (Congo red). The systemic distribution of amyloidoses may produce extracellular deposits in multiple organs (Joachim et al., 1989). In this paper, Clos, Kayed, and Lasagna-Reeves present a novel perspective about the relation of dermis–epidermis–brain and offer a review about amyloid deposits that are central to the strong “brain–skin” connection. This connection starts as early as the sharing a joint embryological origin. Common multipotent embryonic progenitor stem cells from the ectoderm on the surface of the post-gastrulation embryo receive specific signaling from their environment that instruct them to commit to a particular differentiation program which will give rise to the nervous system or skin epithelium (Quan and Hassan, 2005; Fuchs, 2007). Clos, Kayed, and Lasagna-Reeves highlight common “brain–skin” pathophysiological disorders such as the role of presenilin 1 (PS-1) for proteolytic processing of the amyloid precursor protein (APP) which is altered in AD; alteration also found in skin cancers (Xia et al., 2001; Kang et al., 2002). They also draw parallels between neurodegenerative disorders of Parkinsons disease (Lewy bodies, α-synuclein, melanin) and amyotrophic lateral sclerosis (ALS inclusion bodies) which share common features with skin diseases (Hays et al., 2006). In addition, Clos, Kayed, and Lasagna-Reeves are describing transdermal route-of-entry as an elected administration route for potential medications to patients with neurodegenerative diseases such as Rivastigmine (AD and Parkinson), Rotigotine (Parkinson). A favorable coefficient of partition (physiologically based pharmacokinetics, PBPK; Thrall et al., 2002) to the brain via the skin vector seems promising for potential drugs targeting the brain (Zhao et al., 2011). In PDAPP transgenic mice, the immunization with the 42-amino-acid form of the peptide (Aβ42) prevents the development of cerebral β-amyloid-plaque formation, neuritic dystrophy and astrogliosis (Schenk et al., 1999); the transdermal route has also been successfully used without detrimental side effects such as T cell infiltration and cerebral microhemorrhage (Nikolic et al., 2007). Occurrence of the systemic deposition of β-amyloid protein in multiple tissues such as skin or brain infers that the initial amyloid protein may be produced locally in all organs affected or may, as observed in other human amyloidoses, be derived from a common circulating precursor (Joachim et al., 1989). Therefore the transdermal β-amyloid immunization also directly targeting skin β-amyloid deposits may further reduce a potential source for amyloid precursors to other organs such as the brain.

Mild traumatic brain injury and delayed alteration of memory processing

A brain traumatism may result from focal impact upon the head and/or sudden acceleration/deceleration kinetic forces applied to the brain within the rigid skull, or by a complex association of both. Approximately 500,000 to 3 million US cases occur per year. A major problem is that traumatic brain injury (TBI) classified as “mild” may not be reflected by lesions on conventional neuroimaging scans which appear “normal” albeit some mild TBI patients with “normal scans” may express long-term cognitive deficits (Irimia et al., 2012b). This raises overarching questions: would mild TBI result in cognitive deficits years later? How would memory consolidation and long-term potentiation then be affected? Monti et al. attempt to answer some of these questions in the article which appeared in Vol. 5 of Frontiers in Aging Neuroscience (Monti et al., 2013) by studying the relational memory, i.e., the performance of acquiring and retaining memory to construct association of elements of a scene or events in patients having experienced TBI early in their lives. Relational memory impairment is one of the behavioral phenotypes of mild TBI following the selective damage of specific intrinsic connectivity networks, ICNs (Barbey et al., 2015). The interest of Montis study is the determination of post-TBI disrupted networks by visualization of their connectivity which will ultimately serve as patient-personalized diagnostic tools (Irimia et al., 2012a).