New Age Therapy for Alzheimer’s Disease by Neuronal Network Reconstruction

Abstract

Alzheimer's disease (AD) is a recognized incurable neurodegenerative disorder. Clinically prescribed medicines for AD are expected to bring about only slight symptomatic improvement or a delay of its progression. Another strategy, amyloid β (Aβ) lowing agents, has not been successful at memory improvement. We have hypothesized that an improvement in cognitive function requires the construction of neuronal networks, including neurite regeneration and synapse formation; therefore, we have been exploring candidates for radical anti-AD drugs that can restore Aβ-induced neurite atrophy and memory impairment. Our studies found several promising drug candidates that may improve memory dysfunction in AD model mice. The main activity of these drugs is the restoration of damaged axons. Focusing on candidates based on the recovery of neurite atrophy in vitro certainly leads to positive effects on memory improvement also in vivo. This suggests that neuronal network reconstruction may importantly relate to functional recovery in the brain. When identifying the signaling mechanisms of exogenous compounds like natural medicine-derived constituents, molecules directly activated by the compound are hard to be identified. However, the drug affinity responsive target stability (DARTS) analysis may pave the way to an approach to determine the initial molecule of the signaling pathway. Exploring new drug candidates and clarifying their signaling pathways directly relating to neuronal network reconstruction may provide promising therapeutic strategies with which to overcome AD.

Human placenta extract ameliorates memory dysfunction and dendritic atrophy in a 5XFAD mouse model of Alzheimer's disease

“…We hypothesized that reconstruction of damaged neuronal networks may restore neuron function, and many types of extracts and compounds have been screened for inhibition of Aβ‐induced axon and dendrite atrophy. Regrowth of axons and dendrites was found in several cases using herbal drugs and constituents . These bioactive drugs also improved memory functions in AD model mice.…”

White Matter Brain Network Research in Alzheimer’s Disease Using Persistent Features

“…Within these neural networks, even minor mutations can cause serious diseases [4]. In the past several years, some literatures [5][6][7] have begun to explore the treatment of AD and develop drugs from the perspective of structural brain network reconstruction and neuronal circuit repair [8]. Many postmortem histological and in-vivo imaging studies indicate widespread white matter (WM) changes in patients with MCI and AD [9,10].…”

Effects of a Dehydroevodiamine-Derivative on Synaptic Destabilization and Memory Impairment in the 5xFAD, Alzheimer's Disease Mouse Model

“…Currently, drugs used for the treatment of AD only bring some degree of symptomatic relief but fail to cure or delay disease progression (Selkoe, 2011 ). Several studies with regard to inhibiting Aβ aggregation have been reported (Gervais et al, 2001 ; Bilikiewicz and Gaus, 2004 ; Aisen et al, 2006 ; Townsend et al, 2006 ; Santa-Maria et al, 2007 ; Tohda, 2016 ), but no drug has been identified that effectively blocks or reverses the process of AD progression until now. During the last decade, all phase III clinical trials including promising candidates, such as Solanezumab and Verubecestat have failed because of adverse effects and the lack of cognitive improvement (Egan et al, 2018 ; Honig et al, 2018 ).…”