Faculty Bibliography
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1145
Neurofilaments at a glance
PMCID:3516374
PMID: 22956720
ISSN: 0021-9533
CID: 179149
Workgroup on NAPA's scientific agenda for a national initiative on Alzheimer's disease
This report outlines a goal-directed scientific agenda for a national initiative to overcome the Alzheimer's disease (AD) crisis. The statement; which reflects the collective views and recommendations of leaders in AD research; is intended to aid the implementation of the National Alzheimer's Project Act (NAPA)'s National Plan to defeat AD. The primary public policy aims of this 10-year scientific agenda are to discover; validate; and develop: (1) a broad range of technologies; tools and algorithms for early detection of people with symptomatic AD; and asymptomatic individuals at elevated risk for AD and other dementias; and (2) a wide range of interventions to preserve and/or restore health and normal neural function; aiming to maintain independent functioning for as long as possible. The long-term scientific public health objectives of this comprehensive plan are to: (1) reduce the number of people with chronic disabling symptoms who will require prolonged care and; eventually; reduce the number of asymptomatic people at elevated risk for AD/dementia; (2) delay the onset of chronic disability for people with AD and other degenerative brain disorders; and (3) lower the cost and burden of care. The plan calls for significant expansion of research programs to identify and validate the cause(s) and pathogenesis of AD; genetic and epigenetic factors that contribute to AD risk; therapeutic targets that affect disease progression; surrogate biomarkers of AD pathobiology; and technologies for early detection of AD.
PMID: 22748940
ISSN: 1552-5279
CID: 3373292
Peripherin is a subunit of peripheral nerve neurofilaments: implications for differential vulnerability of CNS and peripheral nervous system axons
Peripherin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament triplet proteins [neurofilament light (NFL), medium (NFM), and heavy (NFH) chain] but has an unknown function. The earlier peak expression of peripherin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that peripherin and neurofilament triplets form separate filament systems. However, here, we demonstrate that, despite a postnatal decline in expression, peripherin is as abundant as the triplet in the adult PNS and exists in a relatively fixed stoichiometry with these subunits. Peripherin exhibits a distribution pattern identical to those of triplet proteins in sciatic axons and colocalizes with NFL on single neurofilaments by immunogold electron microscopy. Peripherin also coassembles into a single network of filaments containing NFL, NFM, and NFH with and without alpha-internexin in quadruple- or quintuple-transfected SW13vim(-) cells. Genetically deleting NFL in mice dramatically reduces peripherin content in sciatic axons. Moreover, peripherin mutations has been shown to disrupt the neurofilament network in transfected SW13vim(-) cells. These data show that peripherin and the neurofilament proteins are functionally interdependent. The results strongly support the view that, rather than forming an independent structure, peripherin is a subunit of neurofilaments in the adult PNS. Our findings provide a basis for its close relationship with neurofilaments in PNS diseases associated with neurofilament accumulation.
PMCID:3405552
PMID: 22723690
ISSN: 0270-6474
CID: 170430
New insights into the role of hilar ectopic granule cells in the dentate gyrus based on quantitative anatomic analysis and three-dimensional reconstruction
The dentate gyrus is one of two main areas of the mammalian brain where neurons are born throughout adulthood, a phenomenon called postnatal neurogenesis. Most of the neurons that are generated are granule cells (GCs), the major principal cell type in the dentate gyrus. Some adult-born granule cells develop in ectopic locations, such as the dentate hilus. The generation of hilar ectopic granule cells (HEGCs) is greatly increased in several animal models of epilepsy and has also been demonstrated in surgical specimens from patients with intractable temporal lobe epilepsy (TLE). Herein we review the results of our quantitative neuroanatomic analysis of HEGCs that were filled with Neurobiotin following electrophysiologic characterization in hippocampal slices. The data suggest that two types of HEGCs exist, based on a proximal or distal location of the cell body relative to the granule cell layer, and based on the location of most of the dendrites, in the molecular layer or hilus. Three-dimensional reconstruction revealed that the dendrites of distal HEGCs can extend along the transverse and longitudinal axis of the hippocampus. Analysis of axons demonstrated that HEGCs have projections that contribute to the normal mossy fiber innervation of CA3 as well as the abnormal sprouted fibers in the inner molecular layer of epileptic rodents (mossy fiber sprouting). These data support the idea that HEGCs could function as a "hub" cell in the dentate gyrus and play a critical role in network excitability.
PMCID:3920449
PMID: 22612815
ISSN: 0013-9580
CID: 167509
Calpastatin modulates APP processing in the brains of beta-amyloid depositing but not wild-type mice
We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) beta-amyloidosis, the APP23 mouse, reduces beta-amyloid (Abeta) pathology and Abeta levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Abeta plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Abeta plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with Abeta pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Abeta pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Abeta pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Abeta pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors.
PMCID:3318946
PMID: 22206846
ISSN: 0197-4580
CID: 164336
Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain
J. Neurochem. (2012) 121, 649-661. ABSTRACT: GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase 3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase 3 activation in the 7-day-old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration.
PMCID:3325370
PMID: 22372857
ISSN: 0022-3042
CID: 166032
Identification of CSPalpha Clients Reveals a Role in Dynamin 1 Regulation
Cysteine string protein alpha (CSPalpha), a presynaptic cochaperone for Hsc70, is required for synapse maintenance. Deletion of CSPalpha leads to neuronal dysfunction, synapse loss, and neurodegeneration. We utilized unbiased, systematic proteomics to identify putative CSPalpha protein clients. We found 22 such proteins whose levels are selectively decreased in CSPalpha knockout synapses. Of these putative CSPalpha protein clients, two directly bind to the CSPalpha chaperone complex and are bona fide clients. They are the t-SNARE SNAP-25 and the GTPase dynamin 1, which are necessary for synaptic vesicle fusion and fission, respectively. Using hippocampal cultures, we show that CSPalpha regulates the stability of client proteins and synaptic vesicle number. Our analysis of CSPalpha-dynamin 1 interactions reveals unexpectedly that CSPalpha regulates the polymerization of dynamin 1. CSPalpha, therefore, participates in synaptic vesicle endocytosis and may facilitate exo- and endocytic coupling. These findings advance the understanding of how synapses are functionally and structurally maintained.
PMCID:3328141
PMID: 22500636
ISSN: 0896-6273
CID: 166686
Guidelines for the use and interpretation of assays for monitoring autophagy [Guideline]
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
PMCID:3404883
PMID: 22966490
ISSN: 1554-8627
CID: 181862
Role of vaccine-induced V2 antibodies in protection from HIV infection of recipients in the RV144 clinical vaccine trial [Meeting Abstract]
Objective: Determine the role of V2 antibodies (Abs) in protecting vaccinees from HIV infection after immunization with ALVAC/HIV and clade E and B recombinant gp120 (RV144 vaccine regimen). ELISA reactivity to a V1V2-gp70 fusion protein and a cyclic V2 peptide was assessed using coded plasma specimens from RV144 participants. Results showed that Ab responses were divided into tertiles (low, medium and high). Vaccinees with a high level of Abs to V1V2-gp70 had a lower rate of HIV infection than did those with a low level of Abs. Multivariate logistic regression analysis showed an estimated 71% reduction in the infecton rate for vaccinees with high vs. vaccinees with low Ab responses to V1V2-gp70 (p=0.02). Similarly, compared to the entire placebo group that was HIV- at 26 weeks, the estimated Vaccine Efficacy (VE) was 3% (p=0.91) for subjects with a low V1V2 Ab response, while the estimated VE was 58% (p=0.02) for vaccinees with high V1V2 Abs. The Abs measured by this assay appear to be specific for V2 because no V1 Abs were detected, and epitope mapping data suggest that the epitope recognized by vaccinees' Abs target the midloop region of V2. There was no statistically significant correlation between infection rate and Abs reactive with a cyclic V2 peptide containing the entire V2 loop of the clade E A244 strain. In the primary case control analysis the Ab response to V1V2-gp70 was statistically significantly inversely correlated with infection. While secondary analyses suggest that other immunologic responses (including Abs to other epitopes and cellular responses) may also play a role in protection, the data most strongly support the hypothesis that V2 Abs are important for protection
EMBASE:71184757
ISSN: 1525-4135
CID: 602642
Caloric restriction up-regulates hippocampal CA1 neuroprotective gene expression and reduces amyloid burden in an alzheimer's disease mouse model [Meeting Abstract]
OBJECTIVES/SPECIFIC AIMS: Th ere is no successful treatment or preventative measure for Alzheimer's disease (AD), a disorder characterized by altered amyloidbeta precursor (APP) processing, amyloid-beta (Abeta) aggregation, cell-type specific vulnerability, and cognitive deficits. Caloric restriction (CR) is a noninvasive dietary intervention that may prevent AD pathology. Previous studies have documented CRinduced AD pathology prevention through regional, low-resolution analysis. Th e effects of CR in selectively vulnerable hippocampal CA1 pyramidal neurons have not been demonstrated. METHODS/STUDY POPULATION: Th rough laser capture microdissection (LCM) and microarray analysis, we will investigate gene expression profiles of CA1 neurons isolated during pathology onset and later progression (5 and 15 mos.) from Tg2576 AD mice and nontransgenic littermates maintained on a 30% CR regimen versus ad libitum (AL) feeding. Abeta burden and APP metabolism are assessed as indicators of pathology and for correlation with high-throughput gene expression changes. RESULTS/ANTICIPATED RESULTS: We have identified CR-induced decreases in transcripts implicated in autophagy, synaptic transmission, transcription, and metabolism, as well as CR-specific increases in several kinase and phosphatase transcripts and qualitative reduction in Abeta peptides in CR-Tg2576 mice. We expect further characterization to support the hypothesis that CR induces increased neuronal efficiency, up-regulation of neuroprotective pathways, and decreased Abeta deposition in aged AL-Tg2576 mice. DISCUSSION/SIGNIFICANCE OF IMPACT: Alterations identified by these experiments may serve as targets in the development of therapeutic interventions. Additionally, this work may serve as the basis for further studies of CR-based dietary regimens as an AD pathology prevention option
EMBASE:70804110
ISSN: 1752-8054
CID: 463352
