Nerve Growth Factor-Based Therapy in Alzheimer’s Disease and Age-Related Macular Degeneration

Abstract

Alzheimer’s disease (AD) is an age-associated neurodegenerative disease which is the most common cause of dementia among the elderly. Imbalance in nerve growth factor (NGF) signaling, metabolism, and/or defect in NGF transport to the basal forebrain cholinergic neurons occurs in patients affected with AD. According to the cholinergic hypothesis, an early and progressive synaptic and neuronal loss in a vulnerable population of basal forebrain involved in memory and learning processes leads to degeneration of cortical and hippocampal projections followed by cognitive impairment with accumulation of misfolded/aggregated Aβ and tau protein. The neuroprotective and regenerative effects of NGF on cholinergic neurons have been largely demonstrated, both in animal models of AD and in living patients. However, the development of this neurotrophin as a disease-modifying therapy in humans is challenged by both delivery limitations (inability to cross the blood–brain barrier (BBB), poor pharmacokinetic profile) and unwanted side effects (pain and weight loss). Age-related macular degeneration (AMD) is a retinal disease which represents the major cause of blindness in developed countries and shares several clinical and pathological features with AD, including alterations in NGF transduction pathways. Interestingly, nerve fiber layer thinning, degeneration of retinal ganglion cells and changes of vascular parameters, aggregation of Aβ and tau protein, and apoptosis also occur in the retina of both AD and AMD. A protective effect of ocular administration of NGF on both photoreceptor and retinal ganglion cell degeneration has been recently described. Besides, the current knowledge about the detection of essential trace metals associated with AD and AMD and their changes depending on the severity of diseases, either systemic or locally detected, further pave the way for a promising diagnostic approach. This review is aimed at describing the employment of NGF as a common therapeutic approach to AMD and AD and the diagnostic power of detection of essential trace metals associated with both diseases. The multiple approaches employed to allow a sustained release/targeting of NGF to the brain and its neurosensorial ocular extensions will be also discussed, highlighting innovative technologies and future translational prospects.

Physical Activity Rewires the Human Brain against Neurodegeneration

“…RAFGEF3, also known as EPAC1, is involved in a protective role in suppressing the nucleocytoplasmic transport associated with neurodegeneration in ALS and FTD [ 34 ]. TP53INP2 is highly expressed in sympathetic neuron axons and regulates axon growth by enhancing NGF-TrkA signaling [ 35 ], a pathway implicated mainly in neurodegenerative diseases [ 36 , 37 ].…”

Age-Related Macular Degeneration and Its Association With Neurodegenerative Disorders

“…This enhances the neuroprotective action of NGF on the eye-brain projections as well as on the nucleus basalis. Therefore, this approach can be employed to prevent neurodegenerative changes in the brain and the retina and slow down the progression of AD as well as AMD [31].…”

Amyloidogenesis and Neurotrophic Dysfunction in Alzheimer’s Disease: Do They have a Common Regulating Pathway?

“…Original research exploring the roles of NTFs on AD was initiated in NGF and has accordingly transitioned to clinical trials [ 68 , 69 ]. Although early clinical trials showed that NGF specifically affected AD patients, NGF cannot pass through the blood–brain barrier (BBB), and direct injection of NGF may cause adverse effects, such as pain and weight loss [ 2 , 168 , 169 ]. Tuszynski et al initiated a clinical trial of NGF gene therapy in patients with early-stage AD and confirmed that NGF improves the function of degenerated neurons in the brain tissue of AD patients without obvious side effects [ 68 , 69 ].…”