Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point?

Abstract

Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Lewy body dementia (LBD). We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression.

Dexmedetomidine attenuates the toxicity of β‑amyloid on neurons and astrocytes by increasing BDNF production under the regulation of HDAC2 and HDAC5

“…BDNF participates in the regulation of neuronal survival, differentiation and synaptic plasticity as well as influences formation and consolidation of memory (4,37). Treatment with exogenous BDNF or overexpression of BDNF by adenovirus vector shows protective effect against the apoptosis of neurons and astrocytes (38)(39)(40).…”

“…Neurotrophic factors, together with essential proteins secreted by neurons and glial cells, support neuronal survival, proliferation and maturation as well as maintain the homeostasis of peripheral and central nervous system (4). Brain-derived neurotrophic factor (BDNF) is a major central neurotrophic factor in the central nervous system (4). Reduction of BDNF was reported in the brains of cognitive impairment patients, including AD patients (5,6).…”

“…Reduction of BDNF was reported in the brains of cognitive impairment patients, including AD patients (5,6). As BDNF involves in neuronal survival and neuronal functions, it is proposed that the reduction of BDNF is associated with the pathogenesis of AD (4). Studies performed in vitro and in vivo suggested that BDNF inhibited Aβ-induced neurotoxicity (7)(8)(9).…”

Amyloid‐β oligomers in cellular models of Alzheimer’s disease

“…Decreased expression of neuroactive factors in the brain might account for the development of neurodegenerative and neuropsychiatric disorders (Benussi, Binetti, & Ghidoni, 2017). Galectins are proteins involved in many physiological functions, such as inflammation and immune system.…”

BDNF‐overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro

“…Several studies have shown the involvement of BDNF in the pathogenesis of neurodegenerative diseases and psychiatric disorders, like depression and schizophrenia (Balaratnasingam & Janca, ). Additionally, BDNF acts on cholinergic neurons, which are depleted in Alzheimer's disease (Benussi, Binetti, & Ghidoni, ) and on dopaminergic neurons of the substantia nigra, which are lost in Parkinson's disease (Bhardwaj & Deshmukh, ).…”