AB plays a central role in AD pathogenesis, although there is still a great need to fully define on which of the multiple AB assemblies underlay the neurotoxic properties and the amyloid-forming ability. While soluble oligomers more than fibrillar structures have been implicated in the mechanism(s) of neuronal toxicity, few in vivo experiments and our own recent data indicate that seeding of AB amyloidogenesis in APP transgenic mice can be accelerated by intracerebral infusion of soluble AD brain extracts but not to the same extent by homologous synthetic peptides in various states of aggregation, suggesting the existence of still undefined amyloidogenic co-factors. Two early-onset neurodegenerative conditions, familial British and Danish dementias (FBD and FDD) show extensive pre-amyloid and amyloid deposits, congophilic angiopathy and neurofibrillary tangle pathology, closely resembling AD. The deposited proteins (ABri in FBD and ADan in FDD), nevertheless, differ from AB in length and in primary structure and yet, all species share great propensity to oligomerize, assemble as ion-channel like structures in lipid bi-layers and form fibrils, all suggestive of common pathogenic pathways. We hypothesize that unrelated peptides could adopt similar altered amyloidogenic configurations that trigger comparable downstream detrimental effects in neuronal cells, being capable of accelerating amyloid deposition in vivo when in conjunction with additional amyloidogenic co-factors. Accordingly, we propose:
Aim 1 : to compare oligomeric and fibrillar ABri, ADan and AB assemblies isolated from brains with FBD / FDD / AD as well as from Tg mouse models and determine the structural requirements for synthetic ABri, ADan and AB to form in vitro similar assemblies to those found in vivo;
Aim 2 : to test the functional effect of the oligomeric and fibrillar ABri and ADan species characterized in aim 1 in comparison with analogous AB structures on their differential neurotoxic potential, assessing the induction of specific cell-death mechanisms (activation of initiator and effector caspases, mitochondrial pathways, Ca2+ dysregulation, etc) in ex vivo and in vitro paradigms, validating the results with tissue fractions enriched in oligomeric assemblies as well as synthetic homologues reconstituted in amyloid-depleted tissue extracts;
Aim 3 : to (a) analyze the exogenous amyloidogenic capability of oligomeric/fibrillar AB, ABri and ADan species in vivo in APP and ADanPP Tg animals using intra-hippocampal injections of brain extracts compared with synthetic homologues with analogous oligomerization in the presence/absence of amyloid-depleted brain extracts and (b) conduct a comparative proteomic analysis of the amyloid-inducing extracts to identify common post-translational modifications and/or additional co-factor(s) responsible for the amyloid-inducing activity.

Public Health Relevance

There is extensive experimental data strongly suggesting that amyloid beta (AB) plays a central role in Alzheimer's disease (AD) although basic questions in the pathogenetic mechanisms remain unclear, particularly the role of oligomers and the existence of amyloidogenic co-factors of the disease. To clarify these issues we propose to study two early-onset non-AB neurodegenerative conditions that closely resemble AD: familial British and Danish dementias. The use of these alternative models of neurodegeneration in close comparison with AD cases will help elucidate whether different amyloids trigger common pathogenic mechanisms and are potentially amenable to similar therapeutics strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030539-03
Application #
8049051
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Refolo, Lorenzo
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$330,654
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Cabrera, Erwin; Mathews, Paul; Mezhericher, Emiliya et al. (2018) A? truncated species: Implications for brain clearance mechanisms and amyloid plaque deposition. Biochim Biophys Acta Mol Basis Dis 1864:208-225
Dave, Mandar; Islam, Abul B M M K; Jensen, Roderick V et al. (2017) Proteomic Analysis Shows Constitutive Secretion of MIF and p53-associated Activity of COX-2-/- Lung Fibroblasts. Genomics Proteomics Bioinformatics 15:339-351
Fossati, Silvia; Giannoni, Patrizia; Solesio, Maria E et al. (2016) The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain. Neurobiol Dis 86:29-40
Todd, Krysti; Ghiso, Jorge; Rostagno, Agueda (2016) Oxidative stress and mitochondria-mediated cell death mechanisms triggered by the familial Danish dementia ADan amyloid. Neurobiol Dis 85:130-143
McIntee, Farron L; Giannoni, Patrizia; Blais, Steven et al. (2016) In vivo Differential Brain Clearance and Catabolism of Monomeric and Oligomeric Alzheimer's A? protein. Front Aging Neurosci 8:223
Hernandez-Guillamon, Mar; Mawhirt, Stephanie; Blais, Steven et al. (2015) Sequential Amyloid-? Degradation by the Matrix Metalloproteases MMP-2 and MMP-9. J Biol Chem 290:15078-91
Ghiso, Jorge; Fossati, Silvia; Rostagno, Agueda (2014) Amyloidosis associated with cerebral amyloid angiopathy: cell signaling pathways elicited in cerebral endothelial cells. J Alzheimers Dis 42 Suppl 3:S167-76
Doudevski, Ivo; Rostagno, Agueda; Cowman, Mary et al. (2014) Clusterin and complement activation in exfoliation glaucoma. Invest Ophthalmol Vis Sci 55:2491-9
Todd, Krysti; Fossati, Silvia; Ghiso, Jorge et al. (2014) Mitochondrial dysfunction induced by a post-translationally modified amyloid linked to a familial mutation in an alternative model of neurodegeneration. Biochim Biophys Acta 1842:2457-67
Pinnix, Inga; Ghiso, Jorge A; Pappolla, Miguel A et al. (2013) Major carboxyl terminal fragments generated by ?-secretase processing of the Alzheimer amyloid precursor are 50 and 51 amino acids long. Am J Geriatr Psychiatry 21:474-83

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