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.

Involvement of Kallikrein-Related Peptidases in Nervous System Disorders

“…Likewise, KLK6 can release enkephalin from pro-enkephalin precursors, similarly to the canonical processing performed by the enzyme furin (Silva et al, 2017). It has been proposed that alterations in the enzymatic pathway that controls the maturation of pro-nerve growth factor (NGF) to NGF and its subsequent degradation could be relevant in neurodegenerative processes such as Alzheimer's disease that affect the activity of basal cholinergic neurons of the forebrain (Fahnestock and Shekari, 2019;Mitra et al, 2019;Mufson et al, 2019). A role for KLK8 in the expression of NGF at the skin has been described, but studies directed to show whether that KLK8 or other KLKs influence the bioavailability of NGF in the CNS have not yet been explored (Shingaki et al, 2012).…”

The cholinergic system and treatment response in subtypes of Alzheimer’s disease

“…This NGF treatment was an add-on to ChEI treatment since all patients were already under ChEI treatment. Targeted delivery of NGF has emerged as a potential therapy based on its regenerative effects on the basal forebrain cholinergic neurons [17][18][19]. Our AD patients treated with NGF are part of a study of targeted delivery of NGF to the basal forebrain over 6 or 12 months [20,21].…”

The NGFR100WMutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V

“…Based on this, anti-NGF antibodies are being clinically evaluated to alleviate chronic pain (e.g., due to osteoarthritis; Lane et al, 2010). On the other hand, its robust neurotrophic properties have led to testing NGF as a therapeutic candidate for different conditions including diabetic polyneuropathy (Apfel et al, 1994;Pittenger and Vinik, 2003) and neurodegenerative diseases (Mitra et al, 2019). However, these trials failed due to significant adverse effects, including NGF-induced pain (Apfel, 2002).…”