Innovative Therapy for Alzheimer's Disease-With Focus on Biodelivery of NGF

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with abnormal protein modification, inflammation and memory impairment. Aggregated amyloid beta (Aβ) and phosphorylated tau proteins are medical diagnostic features. Loss of memory in AD has been associated with central cholinergic dysfunction in basal forebrain, from where the cholinergic circuitry projects to cerebral cortex and hippocampus. Various reports link AD progression with declining activity of cholinergic neurons in basal forebrain. The neurotrophic molecule, nerve growth factor (NGF), plays a major role in the maintenance of cholinergic neurons integrity and function, both during development and adulthood. Numerous studies have also shown that NGF contributes to the survival and regeneration of neurons during aging and in age-related diseases such as AD. Changes in neurotrophic signaling pathways are involved in the aging process and contribute to cholinergic and cognitive decline as observed in AD. Further, gradual dysregulation of neurotrophic factors like NGF and brain derived neurotrophic factor (BDNF) have been reported during AD development thus intensifying further research in targeting these factors as disease modifying therapies against AD. Today, there is no cure available for AD and the effects of the symptomatic treatment like cholinesterase inhibitors (ChEIs) and memantine are transient and moderate. Although many AD treatment studies are being carried out, there has not been any breakthrough and new therapies are thus highly needed. Long-term effective therapy for alleviating cognitive impairment is a major unmet need. Discussion and summarizing the new advancements of using NGF as a potential therapeutic implication in AD are important. In summary, the intent of this review is describing available experimental and clinical data related to AD therapy, priming to gain additional facts associated with the importance of NGF for AD treatment, and encapsulated cell biodelivery (ECB) as an efficient tool for NGF delivery.

Keywords: Alzheimer disease; NGF; cholinergic; encapsulated cell biodelivery; neurotrophins.

FIGURE 1

The action of cholinergic basal forebrain neurons in normal and in AD conditions. Cholinergic neurons are known to innervate the cortex and hippocampal regions of the brain. Under normal condition, postsynaptic resident neurons of cortical and hippocampal regions release proNGF, which is processed extracellularly (proNGF to mNGF) and taken up by the presynaptic cholinergic neurons (through TrkA, predominantly). The mNGF is then retrogradely transported within the cholinergic neurons, to the cell nuclei situated in the basal forebrain, to initiate gene expression and signaling cascades. These signaling cascades facilitate the release of acetylcholine from the cholinergic terminals present in cortical or hippocampal regions, thereby initiating cholinergic signaling in these brain regions, which includes anti-inflammatory effects mediated through alpha-7-nicotinic receptors in the glial populations. As mentioned below, this cross-talk is altered during AD in various ways which results in cholinergic degeneration. The figure illustrates that the cholinergic system is affected due to various pathways including the following: (I) Altered NGF maturation, (II) Skewed TrkA/p75 receptor ratio, (III) Inefficient axonal transport and signaling, (IV) Aβ induced modulation of NGF receptors. Apart from inducing death, increased Aβ levels can interact with several NGF receptor types including, alpha-7-nicotinic, and metabotropic receptors, leading to increased inflammation and signaling impairments. (V) Sub-optimal release of acetylcholine leading to glial activation and subsequent inflammatory response. These alterations compromise the availability of mNGF to the basal forebrain cholinergic neurons, which in-turn culminates in hampered cholinergic innervation to cortex and hippocampal regions of the brain. The red crossed out areas represent the affected pathways. Aβ, amyloid β; ACh, acetylcholine; AD, Alzheimer’s disease; NGF, nerve growth factor; TrkA, tyrosine receptor kinase A.

FIGURE 2

The ECB device: The ECB consists of a catheter-like device, which has approximately an 11 mm-long active portion and an outer diameter of 0.72 mm. In the active portion, the genetically modified human cell line (ARPE-19) is depicted growing on the spongy polyvinyl alcohol (PVA) cylindrical scaffold/matrix (a sagittal view is shown), within the semi-permeable polyethersulfone hollow fiber membrane, which allows for the influx of nutrients and the efflux of mature NGF. The membrane is in-turn linked to an inert polyurethane tether, which at its other end is finally attached to the edge of the burr hole. The device can be implanted with precision using a custom-made frame adapter, fitting a standard stereotactic frame. The schematic drawing of an implanted ECB device shows the active portion in orange and the tether in blue.