title: Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-β.
abstract: We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Giuseppe
authors: G
authors: Di Fede
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Marcella
authors: M
authors: Catania
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Emanuela
authors: E
authors: Maderna
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Michela
authors: M
authors: Morbin
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Fabio
authors: F
authors: Moda
authors: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20158 Milan, Italy.
authors: Laura
authors: L
authors: Colombo
authors: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20158 Milan, Italy.
authors: Alessandro
authors: A
authors: Rossi
authors: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20158 Milan, Italy.
authors: Alfredo
authors: A
authors: Cagnotto
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Tommaso
authors: T
authors: Virgilio
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Luisa
authors: L
authors: Palamara
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Margherita
authors: M
authors: Ruggerone
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Giorgio
authors: G
authors: Giaccone
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Ilaria
authors: I
authors: Campagnani
authors: Neuroimmunology and Neuromuscular Disorder Unit, IRCCS Foundation "C. Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Massimo
authors: M
authors: Costanza
authors: Neuroimmunology and Neuromuscular Disorder Unit, IRCCS Foundation "C. Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Rosetta
authors: R
authors: Pedotti
authors: Department of Chemical Engineering, University College London, London WC1E 7JE, UK.
authors: Matteo
authors: M
authors: Salvalaglio
authors: Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20158 Milan, Italy.
authors: Mario
authors: M
authors: Salmona
authors: Neurology V and Neuropathology Unit, IRCCS Foundation "Carlo Besta" Neurological Institute (INCB), Via Celoria 11, 20133 Milan, Italy.
authors: Fabrizio
authors: F
authors: Tagliavini
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D001923:Brain Chemistry; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry*; D066263:Protein Aggregation, Pathological / Q000503:physiopathology*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000138:chemical synthesis*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C505239:amyloid beta-protein (1-6); D054322:tat Gene Products, Human Immunodeficiency Virus