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Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device.

ABSTRACT: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion.Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day.All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable.The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD.ClinicalTrials.gov identifier: NCT01163825 . Registered on 14 Jul 2010.

SUBMITTER: Eyjolfsdottir H

PROVIDER: S-EPMC4936020 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device.

Eyjolfsdottir Helga H Eriksdotter Maria M Linderoth Bengt B Lind Göran G Juliusson Bengt B Kusk Philip P Almkvist Ove O Andreasen Niels N Blennow Kaj K Ferreira Daniel D Westman Eric E Nennesmo Inger I Karami Azadeh A Darreh-Shori Taher T Kadir Ahmadul A Nordberg Agneta A Sundström Erik E Wahlund Lars-Olof LO Wall Anders A Wiberg Maria M Winblad Bengt B Seiger Åke Å Wahlberg Lars L Almqvist Per P

Alzheimer's research & therapy 20160707 1

<h4>Background</h4>Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion.<h4>Methods</h4>Four patients with ...[more]

PMID: 27389402

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Project description:BackgroundThe degeneration of the cholinergic circuit from the basal forebrain to the hippocampus contributes to memory loss in patients suffering from Alzheimer's disease (AD). However, the internal relationships between the acetylcholine (Ach) cycle and memory decline during the early stages of AD currently remain unknown. Here, we investigate the mechanisms underlying the activation of the cholinergic circuit and its impact on learning and memory using APP/PS1 mice models.MethodsNovel object recognition and Morris water maze tests were used to measure learning and memory function. Magnetic resonance spectrum (MRS) imaging was applied to longitudinally track changes in neurochemical metabolism in APP/PS1 mice aged 2, 4, 6, and 8 months. The number of neurons and the deposition of Aβ plaques were measured using Nissl, immunohistochemistry, and Thioflavin S staining. We then employed a chemogenetic strategy to selectively activate the cholinergic circuit from the medial septal nucleus (MS) and the vertical limb of the diagonal band nucleus (VDB) on the basal forebrain to the hippocampus. MRS and immunoblotting techniques were used to measure the neurochemical metabolism levels and cholinergic-related proteins, respectively.ResultsWe found that the levels of choline (Cho) in the basal forebrain were markedly higher compared to other brain regions and that its decrease along with N-acetyl aspartate (NAA) levels in the hippocampus was accompanied by memory deficits in APP/PS1 mice aged 4, 6, and 8 months. In terms of pathology, we observed that the deposition of Aβ plaques gradually aggravated throughout the cerebral cortex and hippocampus in APP/PS1 mice aged 6 and 8 months, while no Aβ deposition was detected in the basal forebrain. In contrast, the activity of choline acetyltransferase (ChAT) enzyme in the basal forebrain was decreased at 6 months of age and the cholinergic neurons were lost in the basal forebrain at 8 months of age. In addition, the activation of the cholinergic circuit from the MS and VDB to the hippocampus using chemical genetics is able to improve learning and reduce memory impairment in APP/PS1 mice. Similarly, the levels of Cho in the basal forebrain; NAA in the hippocampus, as well as the expression of ChAT and vesicular acetylcholine transporter (vAchT) in the basal forebrain; and muscarinic acetylcholine receptor 2 (CHRM2) in the hippocampus all increased.ConclusionsThese findings demonstrate that the neurochemical Cho and NAA of the cholinergic circuit can be used as biomarkers to enable the early diagnosis of AD. In addition, memory impairment in APP/PS1 mice can be attenuated using chemical genetics-driven Ach cycle activity of the cholinergic circuit.

Project description:Cholinergic innervation in the brain is involved in modulating neurovascular function including cerebral blood flow haemodynamics in response to neuronal activity. Cholinergic deficit is associated with pathophysiology in Alzheimer's disease, albeit the aetiology remains to be clarified. In the current study, neocortex cerebral blood flow response to acetylcholine was evaluated by Laser-Doppler Flowmetry (LDF) in 3xTgAD Alzheimer's disease model) and wild-type mice of two age groups. The peak of cerebral blood flow to acetylcholine (i.v.) from baseline levels (% ΔrCBF) was higher in young 3xTgAD versus in wild-type mice (48.35; 95% CI:27.03-69.67 versus 22.70; CI:15.5-29.91, P < 0.05); this was reversed in old 3xTgAD mice (21.44; CI:2.52-40.35 versus 23.25; CI:23.25-39). Choline acetyltransferase protein was reduced in neocortex, while cerebrovascular reactivity to acetylcholine was preserved in young 3×TgAD mice. This suggests endogenous acetylcholine deficit and possible cholinergic denervation from selected cholinergic nuclei within the basal forebrain. The early deposition of tauopathy moieties (mutant hTau and pTau181) and its coincidence in cholinergic cell clusters (occasionaly), were observed at the basal forebrain of 3xTgAD mice including substantia innominate, nucleus Basalis of Meynert and nucleus of horizontal limb diagonal band of Broca. A prominent feature was microglia interacting tauopathy and demonstrated a variety of morphology changes particularly when located in proximity to tauopathy. The microglia ramified phenotype was reduced as evaluated by the ramification index and Fractal analysis. Increased microglia senescence, identified as SASP (senescence-associated secretory phenotype), was colocalization with p16Ink4ɑ, a marker of irreversible cell-cycle arrest in old 3xTgAD versus wild-type mice (P = 0.001). The p16Ink4ɑ was also observed in neuronal cells bearing tauopathy within the basal forebrain of 3xTgAD mice. TNF-ɑ, the pro-inflammatory cytokine elevated persistently in microglia (Pearson's correlation coefficient = 0.62) and the loss of cholinergic cells in vulnerable basal forebrain environment, was indicated by image analysis in 3xTgAD mice, which linked to the cholinergic deficits in neocortex rCBF haemodynamics. Our study revealed the early change of CBF haemodynamics to acetylcholine in 3xTgAD model. As a major effector of brain innate immune activation, microglia SASP with age-related disease progression is indicative of immune cell senescence, which contributes to chronic inflammation and cholinergic deficits at the basal forebrain. Targeting neuroinflammation and senescence may mitigate cholinergic pathophysiology in Alzheimer's disease.

Dataset Information

Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device.

Publications

Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients: application of a second-generation encapsulated cell biodelivery device.

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