Alzheimer's disease: advances in trafficking

Mayeux, Richard; George-Hyslop, Peter St

doi:10.1016/s1474-4422(07)70298-3

Cited by 17 publications

(11 citation statements)

References 10 publications

(10 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Amyloid plaques are not a nonspecific reaction to neurofibrillary pathology because non-AD tauopathies lack amyloid plaques. Further attesting to the specificity of AD-type amyloid plaques is the fact that mutations or duplications in the amyloid precursor protein gene produce the specific features of AD, clinically and pathologically (11–13). Notably, without NFTs or amyloid angiopathy, amyloid plaques are not associated with neurodegeneration (see later).…”

Section: Clinicopathologic Correlation In the Context Of Ad: The Goalmentioning

confidence: 99%

“…As a rule, environmental and genetic factors that predict AD risk also appear to directly potentiate amyloid plaques. These risk factors include head trauma, the ApoE4 allele, Down syndrome, amyloid precursor protein mutations and duplications, SORL1 variants, and mutations in PSEN1 and PSEN2 genes (13). This strong genetic association is relevant to the question of the correlation with cognitive symptoms because all of these alleles are also strong risk factors for dementia.…”

Section: Clinicopathologic Studies In Ad: Review Of the Literaturementioning

confidence: 99%

See 1 more Smart Citation

Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship

Nelson

Braak

Markesbery

2009

J Neuropathol Exp Neurol

528

397

View full text Add to dashboard Cite

Amyloid plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks of Alzheimer disease (AD). There is controversy regarding the use of current diagnostic criteria for AD and whether amyloid plaques and NFTs contribute to cognitive impairment. Because AD is specific to humans, rigorous and comprehensive clinicopathologic studies are necessary to test and refine hypotheses of AD diagnosis and pathogenesis. Neither the clinical nor the pathological aspects of AD evolve in a linear manner, but the predictable sequence of AD pathology allows for stage-based correlations with cognitive deterioration. We discuss subsets of patients with clinical dementia who lack amyloid plaques and NFTs and, conversely, whether individuals without antemortem cognitive impairment can harbor severe AD-type pathological findings at autopsy. There are many medical, technical, and anatomical challenges to clinicopathologic studies in AD. For example, at least two thirds of persons older than 80 years have non-AD brain diseases that can effect on cognitive function. We argue that existing data strongly support the hypothesis that both amyloid plaques and NFTs contribute to cognitive impairment.

show abstract

Section: Clinicopathologic Correlation In the Context Of Ad: The Goalmentioning

confidence: 99%

Section: Clinicopathologic Studies In Ad: Review Of the Literaturementioning

confidence: 99%

Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship

Nelson

Braak

Markesbery

2009

J Neuropathol Exp Neurol

528

397

View full text Add to dashboard Cite

show abstract

“…This was further substantiated by the association of variants in LR11 genes with AD [16]. In vitro , cell culture, knockout mouse models, and clinical investigations all support the concept that LR11 plays a crucial role in APP trafficking and is a key regulator of APP processing [14, 17, 18]. …”

Section: Introductionmentioning

confidence: 98%

Bacterial expression, purification, and model membrane reconstitution of the transmembrane and cytoplasmic domains of the human APP binding protein LR11/SorLA for NMR studies

Wang

Gill

Zhu

et al. 2011

Protein Expression and Purification

View full text Add to dashboard Cite

LR11 (SorLA) is a recently identified neuronal protein that interacts with amyloid precursor protein (APP), a central player in the pathology of the Alzheimer's disease (AD). AD is a neurodegenerative disease and the most common cause of dementia in the elderly. Current estimates suggest that as many as 5.3 million Americans are living with AD. Recent investigations have uncovered the pathophysiological relevance of APP intracellular trafficking in AD. LR11 is of particular importance due to its role in regulating APP transport and processing. LR11 is a type I transmembrane protein and belongs to a novel family of Vps10p receptors. Using a new expression vector, pMTTH, (MBP-MCS1(multiple cloning site)-Thrombin protease cleavage site-MCS2-TEV protease cleavage site-MCS3-His 6 ), we successfully expressed, purified and reconstituted the LR11 transmembrane (TM) and cytoplasmic (CT) domains into bicelles and detergent micelles for NMR structural studies. This new construct allowed us to overcome several obstacles during sample preparation. MBP fused LR11 TM and LR11TMCT proteins are preferably expressed at high levels in E. coli membrane, making a refolding of the protein unnecessary. The C-terminal His-tag allows for easy separation of the target protein from the truncated products from the C-terminus, and provides a convenient route for screening detergents to produce high quality 2D 1 H-15 N TROSY spectra. Thrombin protease cleavage is compatible with most of the commonly used detergents, including a direct cleavage at the E. coli membrane surface. This new MBP construct may provide an effective route for the preparation of small proteins with TM domains.

show abstract

“…Upon releasing their substrates, these cargos traffic back to the TGN to mediate further rounds of cargo-hydrolase transportation. Similar retrograde trafficking of cargo proteins involving signaling molecules such as Wnt and amyloid precursor protein (APP) are thought to be critical for their secretion and function (5,6). Retrograde transportation is highly regulated by the heteropentameric retromer complex that consists of a sorting nexin (SNX) dimer (e.g.…”

mentioning

confidence: 99%

The Phox Domain of Sorting Nexin 5 Lacks Phosphatidylinositol 3-Phosphate (PtdIns(3)P) Specificity and Preferentially Binds to Phosphatidylinositol 4,5-Bisphosphate (PtdIns(4,5)P2)

Koharudin¹,

Furey

Líu

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Subcellular retrograde transport of cargo receptors from endosomes to the trans-Golgi network is critically involved in a broad range of physiological and pathological processes and highly regulated by a genetically conserved heteropentameric complex, termed retromer. Among the retromer components identified in mammals, sorting nexin 5 and 1 (SNX5; SNX1) have recently been found to interact, possibly controlling the membrane binding specificity of the complex. To elucidate how the unique sequence features of the SNX5 phox domain (SNX5-PX) influence retrograde transport, we have determined the SNX5-PX structure by NMR and x-ray crystallography at 1.5 Å resolution. Although the core fold of SNX5-PX resembles that of other known PX domains, we found novel structural features exclusive to SNX5-PX. It is most noteworthy that in SNX5-PX, a long helical hairpin is added to the core formed by a new ␣2-helix and a much longer ␣3-helix. This results in a significantly altered overall shape of the protein. In addition, the unique double PXXP motif is tightly packed against the rest of the protein, rendering this part of the structure compact, occluding parts of the putative phosphatidylinositol (PtdIns) binding pocket. The PtdIns binding and specificity of SNX5-PX was evaluated by NMR titrations with eight different PtdIns and revealed that SNX5-PX preferentially and specifically binds to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ). The distinct structural and PtdIns binding characteristics of SNX5-PX impart specific properties on SNX5, influencing retromer-mediated regulation of retrograde trafficking of transmembrane cargo receptors.The early work on retromer revealed its role in the trafficking of cargo proteins between endosomes and the trans-Golgi network (TGN), 2 although recently, retromer involvement in many other physiological and developmental processes has been uncovered (1, 2). The best studied proteins associated with retromer activity are intracellular sorting receptors such as the yeast vacuolar protein-10 (Vps10) and mammalian mannose 6-phosphate receptors (3, 4). These receptors sort acid hydrolases, enzymes essential for protein degradation, out of the TGN into the yeast vacuole or the mammalian lysosome. Upon releasing their substrates, these cargos traffic back to the TGN to mediate further rounds of cargo-hydrolase transportation. Similar retrograde trafficking of cargo proteins involving signaling molecules such as Wnt and amyloid precursor protein (APP) are thought to be critical for their secretion and function (5, 6). Retrograde transportation is highly regulated by the heteropentameric retromer complex that consists of a sorting nexin (SNX) dimer (e.g. Vps5 and Vps17 in yeast) and a Vps26/ 29/35 trimer (7). In mammals, the binding of the SNX dimer to specific phosphatidylinositol (PtdIns) determines its subcellular membrane association and governs the recruitment of the Vps trimer to endosomal compartments. Mammalian orthologs of the trimer have been biochemically characterized, and th...

show abstract

Alzheimer's disease: advances in trafficking

Cited by 17 publications

References 10 publications

Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship

Neuropathology and Cognitive Impairment in Alzheimer Disease: A Complex but Coherent Relationship

Bacterial expression, purification, and model membrane reconstitution of the transmembrane and cytoplasmic domains of the human APP binding protein LR11/SorLA for NMR studies

The Phox Domain of Sorting Nexin 5 Lacks Phosphatidylinositol 3-Phosphate (PtdIns(3)P) Specificity and Preferentially Binds to Phosphatidylinositol 4,5-Bisphosphate (PtdIns(4,5)P2)

Contact Info

Product

Resources

About