AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models

Selles, Maria Clara; Fortuna, Juliana T.S.; Cercato, Magalí Cecilia; Santos, Luís Eduardo; Domett, Luciana; Bitencourt, Andre L.B.; Carraro, Mariane Favero; Souza, Anderson Santos; Janickova, Helena; Azevedo, Caroline Vieira; Campos, Henrique Correia; Souza, Jorge Marcondes de; Alves-Leon, Soniza Vieira; Prado, Vânia F.; Prado, Marco A. M.; Epstein, Alberto L.; Salvetti, Anna; Longo, Beatriz M.; Arancio, Ottavio; Klein, William L.; Sebollela, Adriano; Felice, Fernanda G. De; Jerusalinsky, Diana; Ferreira, Sérgio T.

doi:10.1016/j.ymthe.2022.11.002

Cited by 9 publications

(3 citation statements)

References 52 publications

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“…The promotion of dense core plaque formation by oxytocin may, at least in part, underlie its beneficial actions, because sequestration of soluble Aβ species into dense core plaques has been suggested recently as a mechanism by which microglia protect the brain from AD-related degeneration, 25 , 26 , 27 and we and others have shown that neutralizing soluble Aβ oligomers rescues memory deficits in APP/PS1 mice. 37 …”

Section: Discussionmentioning

confidence: 99%

Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice

Selles¹,

Fortuna²,

Faria³

et al. 2023

iScience

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Section: Discussionmentioning

confidence: 99%

Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice

Selles¹,

Fortuna²,

Faria³

et al. 2023

iScience

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“…We have previously mentioned preclinical studies reporting the application of AAV5 expressing anti-α-syn antibody fragments [ 60 , 63 , 64 ]. Moreover, AAV vector-mediated delivery of anti-amyloid beta antibody fragments was successfully applied in preclinical models of AD [ 81 ]. Gene-mediated expression of antibody fragments in the brain allows for intracellular production of therapeutic antibodies targeting intracellular toxic protein aggregates.…”

Section: Recombinant Antibody Fragmentsmentioning

confidence: 99%

Recombinant Antibody Fragments for Immunotherapy of Parkinson’s Disease

Manoutcharian,

Gevorkian

2024

BioDrugs

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Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. Multiple genetic and environmental factors leading to progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SN) and consequent depletion of dopamine were described. Current clinical approaches, such as dopamine replacement or deep brain stimulation using surgically implanted probes, provide symptomatic relief but cannot modify disease progression. Therefore, disease-modifying therapeutic tools are urgently needed. Immunotherapy approaches, including passive transfer of protective antibodies and their fragments, have shown therapeutic efficacy in several animal models of neurodegenerative diseases, including PD. Recombinant antibody fragments are promising alternatives to conventional full-length antibodies. Modern computational approaches and molecular biology tools, directed evolution methodology, and the design of tissue-penetrating fusion peptides allowed for the development of recombinant antibody fragments with superior specificity and affinity, reduced immunogenicity, the capacity to target hidden epitopes and cross the blood-brain barrier (BBB), higher solubility and stability, the ability to refold after heat denaturation, and inexpensive large-scale production. In addition, antibody fragments do not induce microglia Fcγ receptor (FcγR)-mediated proinflammatory response and tissue damage in the central nervous system (CNS), because they lack the Fc portion of the immunoglobulin molecule. In the present review, we summarized data on recombinant antibody fragments evaluated as immunotherapeutics in preclinical models of PD and discussed their potential for developing therapeutic and preventive protocols for patients with PD.

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“…Gene therapy methods for AD have reached phase I/II clinical trials using AAV vectors, which can drive long-term gene expression and enhance synaptic function and structure in rodent models with preexisting amyloidosis[ 167 ]. Sustained AAV-mediated overexpression of sAPPα in the brains of elderly APP/PS1dE9 mice with preexisting amyloidosis enhances synaptic function and structure [ 168 ] and reverses behavioral impairments [ 169 ], suggesting that sAPPα can have therapeutic benefits in rodent models even after the beginning of disease [ 170 ]. However, the efficacy of gene editing technology needs improvement to better target amyloid plaques, which are believed to initiate AD neurodegeneration.…”

Section: App-targeted Treatment Strategies In Admentioning

confidence: 99%

Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

2023

Aging dis

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Decades of research have demonstrated an incontrovertible role of amyloid-β (Aβ) in the etiology of Alzheimer's disease (AD). However, the overemphasis on the pathological impacts of Aβ may obscure the role of its metabolic precursor, amyloid precursor protein (APP), as a significant hub in the occurrence and progression of AD. The complicated enzymatic processing, ubiquitous receptor-like properties, and abundant expression of APP in the brain, as well as its close links with systemic metabolism, mitochondrial function and neuroinflammation, imply that APP plays multifaceted roles in AD. In this review, we briefly describe the evolutionarily conserved biological characteristics of APP, including its structure, functions and enzymatic processing. We also discuss the possible involvement of APP and its enzymatic metabolites in AD, both detrimental and beneficial. Finally, we describe pharmacological agents or genetic approaches with the capability to reduce APP expression or inhibit its cellular internalization, which can ameliorate multiple aspects of AD pathologies and halt disease progression. These approaches provide a basis for further drug development to combat this terrible disease.

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AAV-mediated neuronal expression of an scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models

Cited by 9 publications

References 52 publications

Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice

Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice

Recombinant Antibody Fragments for Immunotherapy of Parkinson’s Disease

Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease

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