Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer's Disease

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.

Keywords: Alzheimer’s disease; dementia; early to late stages; mild to severe; pathology; therapeutic strategies.

Figure 1

Summary of major signatures during Alzheimer’s disease (AD) progression. (a) Comparison of brain coronal sections from (i) healthy individual and (ii) AD patient by magnetic resonance imaging (MRI), confirming the significant damage in the AD patient having the reduced brain mass. Reproduced with permission [4]. Copyright 2018, Scientific Reports. (b) Amyloid-beta hypothesis: In early AD, the enzymatic cleavages of amyloid-beta precursor protein (APP) by (i) β-secretase followed by (ii) γ-secretase are dominant and result in the formation of Aβ peptides, which are hydrophobic and prone to form aggregations. (iii) In the early to intermediate stages of AD, the aggregates form into Aβ amyloid fibrils and plaques that further cause phosphorylation of tau, neuronal death, cell loss, and dementia, sequentially [81,84]. (c) Tauopathy: (i) Upon the hyperphosphorylation on the multiple sites of tau, the tau proteins are not able to bind to the microtubules (MT) resulting in the disruption of microtubule structures inside neuronal cells. (ii) They further form oligomeric tau, paired helical filament (PHF), and neurofibrillary tangle (NFT), consequently, and (iii) the accumulation of NTFs in the neurons increases the synaptic impairment and the neuronal death in the middle stage of AD [87,88]. (d) Oxidative stress: (i) Under normal or mild AD conditions, antioxidation mechanisms (e.g., mitochondrial redox cycles) can reduce the oxidative stress caused by Aβ and tau aggregations. (ii) In later stages of AD, however, the accumulation of Aβ and tau triggers the excessive production of oxidative stress and reduces the antioxidation mechanism of mitochondria or antioxidant enzymes, which increases the neuronal death [89,90]. (e) Neuroinflammation: (i) In the early stages, innate immune cells obtain phenotypes (e.g., M2 microglia, A2 astrocyte, etc.) serving neuroprotective roles, such as the removal of Aβ and tau aggregations and the production of anti-inflammatory cytokines, as well as neurotrophic factors. (ii) In the later AD stages, on the other hand, the population of proinflammatory immune cells (e.g., M1 microglia, A1 astrocyte, etc.) becomes dominant and increases the risk of AD by producing several neurotoxic mediators, such as oxidative sources and proinflammatory cytokines/chemokines [91,92].