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.
Highlights
As an integral part/extension of the central nervous system (CNS), ocular structures display several cytological, anatomical, and developmental similarities with the brain so that the retina and cerebral areas, receiving directly and indirectly its inputs, constitute the so-called “eye–brain connection” (Erskine and Herrera, 2014; Tirassa et al, 2018)
Chronic activation of inflammatory pathway(s), mitochondrial impairment, vascular changes, neurotrophin(s) imbalance, protein quality control deficits and proteostasis, metal ion dyshomeostasis, genetics causes, or a combination of them are proposed to be involved in age-related disorders featured by brain and retinal degeneration, including Alzheimer’s disease (AD) and age-related macular degeneration (AMD; Kaarniranta et al, 2011; Masuzzo et al, 2016; Xu et al, 2018; Acevedo et al, 2019; Micera et al, 2019; Mufson et al, 2019; Wang and Mao, 2021)
The extracellular neuritic plaques, composed of β-amyloid (Aβ), and the intracellular neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau protein, are the two key neuropathological hallmarks associated with this disease
Summary
As an integral part/extension of the central nervous system (CNS), ocular structures display several cytological, anatomical, and developmental similarities with the brain so that the retina and cerebral areas, receiving directly (visual system) and indirectly (amygdala, hippocampus, and other hypothalamic nuclei) its inputs, constitute the so-called “eye–brain connection” (Erskine and Herrera, 2014; Tirassa et al, 2018). The extracellular neuritic plaques, composed of β-amyloid (Aβ), and the intracellular neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau protein, are the two key neuropathological hallmarks associated with this disease. Both Aβ plaques and NFTs impair synaptic plasticity and neural circuit networks causing the clinical symptoms of progressive memory loss (Spires-Jones and Hyman, 2014; Masters et al, 2015). Accumulation of insoluble extracellular aggregates called drusen in the retina, degeneration of retinal pigment epithelium (RPE) cells, and choroidal neovascularization (CNV) manifest in AMD-suffering subjects leading to irreversible loss of vision (Ambati and Fowler, 2012; van Lookeren Campagne et al, 2014)
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