Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Ittner, Lars M.; Klugmann, Matthias; Ke, Yazi D.

doi:10.1111/bph.14637

Cited by 24 publications

(15 citation statements)

References 177 publications

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“…Adeno-associated viruses (AAVs) can mediate gene transfer directly to the CNS ( Ittner et al, 2019 ). AAVs have become the most widely used gene therapy vectors for the CNS due of their safety, nonpathogenic nature, and capability to infect dividing and quiescent cells in vivo , particularly neurons ( Ittner et al, 2019 ). An ongoing trial is scheduled to start soon to test the safety of AAV-APOE2 expression in APOE4 carriers 1 .…”

Section: Apoe-targeted Therapies For Loadmentioning

confidence: 99%

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

2021

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by extracellular amyloid β (Aβ) and intraneuronal tau protein aggregations. One risk factor for developing AD is the APOE gene coding for the apolipoprotein E protein (apoE). Humans have three versions of APOE gene: ε2, ε3, and ε4 allele. Carrying the ε4 allele is an AD risk factor while carrying the ε2 allele is protective. ApoE is a component of lipoprotein particles in the plasma at the periphery, as well as in the cerebrospinal fluid (CSF) and in the interstitial fluid (ISF) of brain parenchyma in the central nervous system (CNS). ApoE is a major lipid transporter that plays a pivotal role in the development, maintenance, and repair of the CNS, and that regulates multiple important signaling pathways. This review will focus on the critical role of apoE in AD pathogenesis and some of the currently apoE-based therapeutics developed in the treatment of AD.

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Section: Apoe-targeted Therapies For Loadmentioning

confidence: 99%

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

2021

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“…chemogenetics 20 ). AAVs have also been used to create animal models of CNS disorders by delivering pathogenic constructs to brain regions of interest, such as the overexpression of a-synuclein in the striatum that results in progressive neurodegeneration and motor phenotypes characteristic of Parkinson's disease [21][22][23] , or of expanded glutamine-encoding CAG repeats to create a striatal degeneration model of Huntington's disease (HD) 21,24,25 , or of amyloid beta to reproduce features of Alzheimer's disease 26,27 .…”

Section: Introductionmentioning

confidence: 99%

Intra-striatal AAV2.retro administration leads to extensive retrograde transport in the rhesus macaque brain: implications for disease modeling and therapeutic development

Weiss

Liguore

Domire

et al. 2020

Preprint

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ABSTRACTRecently, AAV2.retro, a new capsid variant capable of efficient retrograde transport in brain, was generated in mice using a directed evolution approach. However, it remains unclear to what degree transport will be recapitulated in the substantially larger and more complex nonhuman primate (NHP) brain. Here, we compared the biodistribution of AAV2.retro with its parent serotype, AAV2, in adult macaques following delivery into the caudate and putamen, brain regions which comprise the striatum. While AAV2 transduction was primarily limited to the injected brain regions, AAV2.retro transduced cells in the striatum and in dozens of cortical and subcortical regions with known striatal afferents. We then evaluated the capability of AAV2.retro to deliver disease-related gene cargo to biologically-relevant NHP brain circuits by packaging a fragment of human mutant HTT, the causative gene mutation in Huntington’s disease. Following intra-striatal delivery, pathological mHTT-positive protein aggregates were distributed widely among cognitive, motor, and limbic cortico-basal ganglia circuits. Together, these studies demonstrate strong retrograde transport of AAV2.retro in NHP brain, highlight its utility in developing novel NHP models of brain disease and suggest its potential for querying circuit function and delivering therapeutic genes in the brain, particularly where treating dysfunctional circuits, versus single brain regions, is warranted.

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“…6), so the AAV-DJ8 could deliver genes into neuron cells and other non-neuron cells (such as astrocytes and interneurons). AAV gene therapy has been used in many neurodegenerative diseases, such as Parkinson's disease, Alzheimer disease and SMA [28][29][30]. Intracranial or intrathecal injection of AAV serotype 1, 2, 5, 8 and 9 can cross the blood-brain barrier and precisely target the local population of NSCs and non-neural cells such as astrocytes and oligodendrocytes [31].…”

Section: Discussionmentioning

confidence: 99%

Breast Carcinoma-amplified Sequence 2 Regulates Adult Neurogenesis via β-catenin

Chen¹

2021

Preprint

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Background Breast carcinoma-amplified sequence 2 (BCAS2) regulates β-catenin gene splicing. The conditional knockout of BCAS2 expression in the forebrain (BCAS2 cKO) of mice confers impaired learning and memory along with decreased β-catenin expression. Because β-catenin reportedly regulates adult neurogenesis, we wondered whether BCAS2 could regulate adult neurogenesis via β-catenin. Methods BCAS2 regulating neurogenesis was investigated by characterizing BCAS2 cKO mice. Also, lentivirus-shBCAS2 was intracranially injected into the hippocampus of wild-type mice to knock down BCAS2 expression. We evaluated the rescue effects of BCAS2 cKO by intracranial injection of adeno-associated virus encoding BCAS2 (AAV-DJ8-BCAS2) and AAV-β-catenin gene therapy. Results To show that BCAS2-regulating adult neurogenesis via β-catenin, first, BCAS2 cKO mice showed low SRY-box 2–positive (Sox2+) neural stem cell proliferation and doublecortin-positive (DCX+) immature neurons. Second, stereotaxic intracranial injection of lentivirus-shBCAS2 knocked down BCAS2 in the hippocampus of wild-type mice, and we confirmed the BCAS2 regulation of adult neurogenesis via β-catenin. Third, AAV-DJ8-BCAS2 gene therapy in BCAS2 cKO mice reversed the low proliferation of Sox2+ neural stem cells and the decreased number of DCX+ immature neurons with increased β-catenin expression. Moreover, AAV-β-catenin gene therapy restored neuron stem cell proliferation and immature neuron differentiation, which further supports BCAS2 regulating adult neurogenesis via β-catenin. In addition, cells targeted by AAV-DJ8 injection into the hippocampus included Sox2 and DCX immature neurons, interneurons, and astrocytes. BCAS2 may regulate adult neurogenesis by targeting Sox2+ and DCX+ immature neurons for autocrine effects and interneurons or astrocytes for paracrine effects. Conclusions BCAS2 can regulate adult neurogenesis in mice via β-catenin.

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Adeno‐associated virus‐based Alzheimer's disease mouse models and potential new therapeutic avenues

Cited by 24 publications

References 177 publications

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics

Intra-striatal AAV2.retro administration leads to extensive retrograde transport in the rhesus macaque brain: implications for disease modeling and therapeutic development

Breast Carcinoma-amplified Sequence 2 Regulates Adult Neurogenesis via β-catenin

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