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Clearance systems in the brain-implications for Alzheimer diseaser

Tarasoff-Conway, Jenna M; Carare, Roxana O; Osorio, Ricardo S; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V; Frangione, Blas; Blennow, Kaj; Menard, Joel; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J
PMID: 27020556
ISSN: 1759-4766
CID: 2162882

Clearance systems in the brain-implications for Alzheimer disease

Tarasoff-Conway, Jenna M; Carare, Roxana O; Osorio, Ricardo S; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V; Frangione, Blas; Blennow, Kaj; Menard, Joel; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J
Accumulation of toxic protein aggregates-amyloid-beta (Abeta) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Abeta accumulation has been hypothesized to result from an imbalance between Abeta production and clearance; indeed, Abeta clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Abeta is cleared from the brain. Extracellular Abeta deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Abeta (eAbeta) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAbeta from the brain, any alteration to their function could contribute to AD. An understanding of Abeta clearance might provide strategies to reduce excess Abeta deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Abeta.
PMID: 26195256
ISSN: 1759-4766
CID: 1683822

Increased CSF Matrix Metalloproteinase-9 (MMP-9) and Reduced White Matter Integrity with Increasing Age in Late-life Major Depression [Meeting Abstract]

Pomara, Nunzio; Reichert, Chelsea; Lee, Sang Han; Nierenberg, Jay; Halliday, Matthew R; Sagare, Abhay P; Frangione, Blas; Zlokovic, Berislav V
ISSN: 1740-634x
CID: 1424592

Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown

Halliday, Matthew R; Pomara, Nunzio; Sagare, Abhay P; Mack, Wendy J; Frangione, Blas; Zlokovic, Berislav V
PMID: 24030206
ISSN: 2168-6149
CID: 538882

Greater risk of Alzheimer's disease in older adults with insomnia [Letter]

Osorio, Ricardo S; Pirraglia, Elizabeth; Aguera-Ortiz, Luis F; During, Emmanuel H; Sacks, Hayley; Ayappa, Indu; Walsleben, Joyce; Mooney, Anne; Hussain, Asad; Glodzik, Lidia; Frangione, Blas; Martinez-Martin, Pablo; de Leon, Mony J
PMID: 21391952
ISSN: 1532-5415
CID: 134223

Inherited Amyloidoses and Neurodegeneration: Familial British Dementia and Familial Danish Dementia

Chapter by: Revesz, T; Rostagno, A; Plant, G; Lashley, T; Frangione, B; Ghiso, J; Holton, JL
in: Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders by
pp. 439-445
CID: 841302


Tomidokoro Y; Tamaoka A; Holton JL; Lashley T; Frangione B; Revesz T; Rostagno A; Ghiso J
Amyloid molecules harboring pyroglutamate (pGlu) residue at the N-termini are considered to be important for the development of cerebral amyloidosis such as Alzheimer's disease and thought to be either spontaneously generated or being catalyzed by glutaminyl cyclase. Familial British dementia (FBD) is an autosomal dominant form of dementia neuropathologically characterized by parenchymal amyloid and preamyloid deposits, extensive cerebral amyloid angiopathy, and neurofibrillary tangles. FBD is caused by a stop to Arg mutation in the BRI2 gene, generating de novo created amyloid molecule ABri which accumulates in FBD brains but is not present in the normal population. Soluble ABri molecules present in the circulation of carriers of the BRI2 mutation are 34 amino acids long exclusively harboring Glu residue at the N-termini (ABri1-34E), whereas water- and formic acid-soluble ABri molecules extracted from FBD brains have abundant ABri species bearing pGlu residue (ABri1-34pE), suggesting that pyroglutamate formation occurs at the site of deposition. In order to further clarify the mechanism (s) of ABri deposition, we studied whether pyroglutamate formation indeed occurs outside the central nervous system taking advantage that FBD is also a systemic amyloidosis. Soluble and fibrillar ABri molecules extracted from systemic organs and analyzed biochemically using a combination of immunoprecipitation, mass spectrometry, and western blot analysis were oligomeric in size and contained a large proportion of ABri1-34pE. The data indicate that pyroglutamate formation at the N-termini of ABri molecules is an early step in the process of FBD amyloid deposition, and its formation is not restricted to the central nervous system
PMID: 21037969
ISSN: 0439-1721
CID: 138254


Ghiso J; Tomidokoro Y; Revesz T; Frangione B; Rostagno A
Cerebral amyloid angiopathy (CAA) is increasingly recognized as a major contributor of Alzheimer's disease (AD) pathogenesis. To date, vascular deposits and not parenchymal plaques appear more sensitive predictors of dementia. Amyloid deposition in and around cerebral blood vessels plays a central role in a series of response mechanisms that lead to changes in the integrity of the blood-brain barrier, extravasations of plasma proteins, edema formation, release of inflammatory mediators and matrix metalloproteases which, in turn, produce partial degradation of the basal lamina with the potential to develop hemorrhagic complications. The progressive buildup of amyloid deposits in and around blood vessels chronically limits blood supply and causes focal deprivation of oxygen, triggering a secondary cascade of metabolic events several of which involve the generation of nitrogen and oxygen free radicals with consequent oxidative stress and cell toxicity. Many aspects of CAA in early- and late-onset AD -the special preference of Abeta40 to deposit in the vessel walls, the favored vascular compromise associated with many Abeta genetic variants, the puzzling observation that some of these vasculotropic variants solely manifest with recurrent hemorrhagic episodes while others are mainly associated with dementia- await clarification. Non-Abeta cerebral amyloidoses reinforce the viewpoint that plaque burden is not indicative of dementia while highlighting the relevance of nonfibrillar lesions and vascular involvement in the disease pathogenesis. The lessons learned from the comparative study of Abeta and non-Abeta cerebral amyloidosis provide new avenues and alternative models to study the role of amyloid in the molecular basis of neurodegeneration
PMID: 21037967
ISSN: 0439-1721
CID: 138253

A-beta derivative vaccination in old mouse lemur primates [Meeting Abstract]

Mestre-Frances, Nadine; Trouche, Stephanie G; Boutajangout, Allal; Asuni, Ayodeji; Arribat, Yoan; Rouland, Sylvie; Wisniewski, Thomas; Frangione, Blas; Maurice, Tangui; Sigurdsson, Einer M; Verdier, Jean Michel
ISSN: 1552-5279
CID: 2399872

Iowa variant of familial Alzheimer's disease: accumulation of posttranslationally modified AbetaD23N in parenchymal and cerebrovascular amyloid deposits

Tomidokoro, Yasushi; Rostagno, Agueda; Neubert, Thomas A; Lu, Yun; Rebeck, G William; Frangione, Blas; Greenberg, Steven M; Ghiso, Jorge
Mutations within the amyloid-beta (Abeta) sequence, especially those clustered at residues 21-23, which are linked to early onset familial Alzheimer's disease (AD), are primarily associated with cerebral amyloid angiopathy (CAA). The basis for this predominant vascular amyloid burden and the differential clinical phenotypes of cerebral hemorrhage/stroke in some patients and dementia in others remain unknown. The AbetaD23N Iowa mutation is associated with progressive AD-like dementia, often without clinically manifested intracerebral hemorrhage. Neuropathologically, the disease is characterized by predominant preamyloid deposits, severe CAA, and abundant neurofibrillary tangles in the presence of remarkably few mature plaques. Biochemical analyses using a combination of immunoprecipitation, mass spectrometry, amino acid sequence, and Western blot analysis performed after sequential tissue extractions to separately isolate soluble components, preamyloid, and fibrillar amyloid species indicated that the Iowa deposits are complex mixtures of mutated and nonmutated Abeta molecules. These molecules exhibited various degrees of solubility, were highly heterogeneous at both the N- and C-termini, and showed partial aspartate isomerization at positions 1, 7, and 23. This collection of Abeta species-the Iowa brain Abeta peptidome-contained clear imprints of amyloid clearance mechanisms yet highlighted the unique neuropathological features shared by a non-Abeta cerebral amyloidosis, familial Danish dementia, in which neurofibrillary tangles coexist with extensive pre-amyloid deposition in the virtual absence of fibrillar lesions. These data therefore challenge the importance of neuritic plaques as the sole contributors for the development of dementia
PMID: 20228223
ISSN: 1525-2191
CID: 108922