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1.
Mol Cell Neurosci ; 130: 103950, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38901655

RESUMO

Amyloid beta (Aß) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist in states that range from soluble monomers and oligomers/protofibrils to insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version of lecanemab that preferentially binds to soluble Aß protofibrils, in aged transgenic mice (Tg2576) with Aß pathology. Female Tg2576 mice (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks or for 18 weeks, with or without a subsequent 12-week off-treatment period. Aß protofibril levels were significantly lower in mAb158-treated animals at both 4 and 18 weeks, while longer treatment duration (18 weeks) was required to observe significantly lower Aß42 levels in insoluble brain fractions and lower Aß plaque load. Following the off-treatment period, comparison of the vehicle- and mAb158-treated mice demonstrated that the Aß protofibril levels, insoluble Aß42 levels and Aß plaque load remained significantly lower in mAb158-treated animals, as compared with age-matched controls. However, there was a significant increase of brain accumulation of both the Aß protofibril levels, insoluble Aß42 levels and Aß plaque load after treatment cessation. Thus, repeated mAb158 treatment of aged Tg2576 mice first reduced Aß protofibril levels within 4 weeks of treatment, which then was followed by a reduction of amyloid plaque pathology within 18 weeks of treatment. These effects were maintained 12 weeks after the final dose, indicating that mAb158 had a disease-modifying effect on the Aß pathology in this mouse model. In addition, brain accumulation of both Aß protofibril levels and amyloid pathology progressed after discontinuation of the treatment which supports the importance of continued treatment with mAb158 to maintain the effects on Aß pathology.

2.
Neurobiol Dis ; 161: 105543, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34737044

RESUMO

A growing body of evidence suggests that aggregated α-synuclein, the major constituent of Lewy bodies, plays a key role in the pathogenesis of Parkinson's disease and related α-synucleinopathies. Immunotherapies, both active and passive, against α-synuclein have been developed and are promising novel treatment strategies for such disorders. Here, we report on the humanization and pharmacological characteristics of ABBV-0805, a monoclonal antibody that exhibits a high selectivity for human aggregated α-synuclein and very low affinity for monomers. ABBV-0805 binds to a broad spectrum of soluble aggregated α-synuclein, including small and large aggregates of different conformations. Binding of ABBV-0805 to pathological α-synuclein was demonstrated in Lewy body-positive post mortem brains of Parkinson's disease patients. The functional potency of ABBV-0805 was demonstrated in several cellular assays, including Fcγ-receptor mediated uptake of soluble aggregated α-synuclein in microglia and inhibition of neurotoxicity in primary neurons. In vivo, the murine version of ABBV-0805 (mAb47) displayed significant dose-dependent decrease of α-synuclein aggregates in brain in several mouse models, both in prophylactic and therapeutic settings. In addition, mAb47 treatment of α-synuclein transgenic mice resulted in a significantly prolonged survival. ABBV-0805 selectively targets soluble toxic α-synuclein aggregates with a picomolar affinity and demonstrates excellent in vivo efficacy. Based on the strong preclinical findings described herein, ABBV-0805 has been progressed into clinical development as a potential disease-modifying treatment for Parkinson's disease.


Assuntos
Anticorpos Monoclonais , Doença de Parkinson , Sinucleinopatias , Animais , Anticorpos Monoclonais/uso terapêutico , Humanos , Longevidade , Camundongos , Camundongos Transgênicos , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Sinucleinopatias/terapia , alfa-Sinucleína/metabolismo
3.
Brain ; 137(Pt 2): 553-64, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24259408

RESUMO

Alzheimer's disease is characterized by the accumulation of amyloid deposits in the brain and the progressive loss of cognitive functions. Although the precise role of amyloid-ß in disease progression remains somewhat controversial, many efforts to halt or reverse disease progression have focussed on reducing its synthesis or enhancing its removal. It is believed that brain and peripheral soluble amyloid-ß are in equilibrium and it has previously been hypothesized that a reduction in peripheral amyloid-ß can lower brain amyloid-ß, thereby reducing formation of plaques predominantly composed of insoluble amyloid-ß; the so-called peripheral sink hypothesis. Here we describe the use of an amyloid-ß degrading enzyme, the endogenous metallopeptidase neprilysin, which is fused to albumin to extend plasma half-life and has been engineered to confer increased amyloid-ß degradation activity. We used this molecule to investigate the effect of degradation of peripheral amyloid-ß on amyloid-ß levels in the brain and cerebrospinal fluid after repeated intravenous dosing for up to 4 months in Tg2576 transgenic mice, and 1 month in rats and monkeys. This molecule proved highly effective at degradation of amyloid-ß in the periphery but did not alter brain or cerebrospinal fluid amyloid-ß levels, suggesting that the peripheral sink hypothesis is not valid and is the first time that this has been demonstrated in non-human primates.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neprilisina/administração & dosagem , Animais , Feminino , Humanos , Injeções Intravenosas , Macaca fascicularis , Masculino , Camundongos , Camundongos Transgênicos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
4.
Curr Pharm Des ; 20(15): 2484-90, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23859556

RESUMO

Alzheimer's disease (AD) is a slowly progressing disease and the evaluation of clinical effects of candidate drugs requires large clinical cohorts as well as long treatment trials. There is a great need for central biomarkers and translatable pre-clinical models to provide early indication of treatment effects. We set out to evaluate the guinea pig as a clinically translatable model looking at Aß peptides. Our data demonstrate homology between ß-amyloid (Aß) peptide pattern in cerebrospinal fluid (CSF) from human and guinea pig. To further evaluate the model a novel γ-secretase modulator was used. Dose and time response studies confirm the modulatory properties with a statistically significant decrease in relative levels of Aß1-40, Aß1-42 and increase in Aß1-37 already one hour after administration. We suggest that the guinea pig is a compelling pre-clinical model for evaluating and translating central effects on Aß peptides in CSF after treatment. Further quantitative data are needed to confirm our data together with data from clinical trials in order to back translate and validate our findings.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide , Animais , Modelos Animais de Doenças , Cobaias , Humanos , Masculino
5.
J Neurosci ; 33(24): 10075-84, 2013 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-23761903

RESUMO

Aß, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). ß-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aß peptides. Small molecule BACE1 inhibitors are expected to decrease Aß-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aß production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.


Assuntos
Doença de Alzheimer/patologia , Amiloide/metabolismo , Inibidores Enzimáticos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Córtex Cerebral/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Feminino , Cobaias , Humanos , Isoindóis/farmacologia , Isoindóis/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Fragmentos de Peptídeos/metabolismo , Piridonas/farmacologia , Piridonas/uso terapêutico , Fatores de Tempo
6.
Pharmacol Res Perspect ; 1(2): e00012, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25505567

RESUMO

According to the "amyloid hypothesis," accumulation of amyloid beta (Aß) peptides in the brain is linked to the development of Alzheimer's disease. The aims of this investigation were to develop a model for the age-dependent amyloid accumulation and to quantify the age- and treatment-duration-dependent efficacy of the γ-secretase inhibitor MRK-560 in the Tg2576 transgenic mouse model of amyloid deposition. Soluble and insoluble Aß40 and Aß42 brain concentrations were compiled from multiple naïve, vehicle, and MRK-560-treated animals. The age of Tg2576 mice in the studies ranged between 3.5 and 26 months. Single doses of MRK-560 inhibited soluble Aß40 levels in animals up to 9 months old. In contrast, MRK-560 did not cause significant acute effects on soluble Aß40 levels in animals older than 13 months. Absolute levels of Aß variants increased exponentially over age and reached a plateau at ∼20 months. In the final model, it was assumed that MRK-560 inhibited the Aß production rate with an Aß level-dependent IC50.The age-dependent increase in Aß levels was best described by a logistic model that stimulated the production rate of soluble Aß. The increase in insoluble Aß was defined as a function of soluble Aß by using a scaling factor and a different turnover rate. The turnover half-life for insoluble Aß was estimated at 30 days, explaining that at least a 4-week treatment in young animals was required to demonstrate a reduction in insoluble Aß. Taken together, the derived knowledge could be exploited for an improved design of new experiments in Tg2576 mice.

7.
Eur J Neurosci ; 36(9): 3165-72, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22958226

RESUMO

Neuropil deposition of beta-amyloid (Aß) peptides is believed to be a key event in the neurodegenerative process of Alzheimer's disease (AD). An early and consistent clinical finding in AD is olfactory dysfunction with associated pathology. Interestingly, transgenic amyloid precursor protein (Tg2576) mice also show early amyloid pathology in olfactory regions. Moreover, a recent study indicates that axonal transport is compromised in the olfactory system of Tg2576 mice, as measured by manganese-enhanced magnetic resonance imaging (MEMRI). Here we tested whether the putative axonal transport deficit in the Tg2576 mouse model improves in response to a selective gamma-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560). Tg2576 mice or wild-type (WT) littermates were treated daily with MRK-560 (30 µmol/kg) or vehicle for 4 (acute) or 29 days (chronic). The subsequent MEMRI analysis revealed a distinct axonal transport dysfunction in the Tg2576 mice compared with its littermate controls. Interestingly, the impairment of axonal transport could be fully reversed by chronic administration of MRK-560, in line with the significantly lowered levels of both soluble and insoluble forms of Aß found in the brain and olfactory bulbs (OBs) following treatment. However, no improvement of axonal transport was observed after acute treatment with MRK-560, where soluble but not insoluble forms of Aß were reduced in the brain and OBs. The present results show that axonal transport is impaired in Tg2576 mice compared with WT controls, as measured by MEMRI. Chronic treatment in vivo with a gamma-secretase inhibitor, MRK-560, significantly reduces soluble and insoluble forms of Aß, and fully reverses the axonal transport dysfunction.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Transporte Axonal/efeitos dos fármacos , Sulfonamidas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Transporte Axonal/genética , Encéfalo/metabolismo , Imageamento por Ressonância Magnética , Manganês , Camundongos , Camundongos Transgênicos , Bulbo Olfatório/metabolismo
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