Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, typically showing progressive neurodegeneration in aging brains. The key signatures of the AD progression are the deposition of amyloid-beta (Aβ) peptides, the formation of tau tangles, and the induction of detrimental neuroinflammation leading to neuronal loss. However, conventional pharmacotherapeutic options are merely relying on the alleviation of symptoms that are limited to mild to moderate AD patients. Moreover, some of these medicines discontinued to use due to either the insignificant effectiveness in improving the cognitive impairment or the adverse side effects worsening essential bodily functions. One of the reasons for the failure is the lack of knowledge on the underlying mechanisms that can accurately explain the major causes of the AD progression correlating to the severity of AD. Therefore, there is an urgent need for the better understanding of AD pathogenesis and the development of the disease-modifying treatments, particularly for severe and late-onset AD, which have not been covered thoroughly. Here, we review the underlying mechanisms of AD progression, which have been employed for the currently established therapeutic strategies. We believe this will further spur the discovery of a novel disease-modifying treatment for mild to severe, as well as early- to late-onset, AD.

Highlights

  • Alzheimer’s disease is a worldwide public health concern as it is the most common cause of dementia, occasionally found in elderly [1,2]

  • We explore details on molecular and cellular mechanisms governing Alzheimer’s disease (AD) progression and their contributions to the development of current and new promising treatment modalities targeting mild to severe AD

  • Klementieva et al discovered the significant accumulation of Aβ42 aggregates in synaptic compartments, which developed into Aβ plaques and induced the synaptic impairment in amyloid-beta precursor protein (APP)/PS1 mice brains, demonstrating that the deposition of Aβ on the synapsis initiated the AD pathology [97]

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Summary

Introduction

Alzheimer’s disease is a worldwide public health concern as it is the most common cause of dementia, occasionally found in elderly [1,2]. Primary pathological hallmarks of AD in the molecular level involve the accumulation of Aβ plaques [10,11] and neurofibrillary tangles (NFTs) [12,13], composed of dystrophic neurites, and hyperphosphorylated tau. These aggregates are gradually building up the intra and extracellular spaces of neurons, which block neurogenesis, as well as nutrient and oxygen supplies to neuronal cells, leading to neurodegenerative process [14].

Targeting tauopathy
Central Hypothesis for AD Pathogenesis
Tau Hypothesis
Oxidative Stress
Neuroinflammation
Inhibition of Aβ Cascade
Passive Immunotherapy Targeting Aβ
Inhibition of Aβ Aggregation
Challenges
Inhibition of Hyperphosphorylation in Tau
Inhibition of Tau Aggregation
Inhibition of Tau Activity
Neuroinflammatory Modulation
TREM2 Pathway
TLR Pathway
Anti-Inflammatory Therapy Targeting Adaptive Immune System
Increase of Neurotrophic Effects by Peptide Mimetics
Conversion of Glial Cells to Neuronal Cells
Transplanting Stem Cells into Brains
Findings
Outlook
Full Text
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