Reviewing the Current State of Immunotherapy for Alzheimer's Disease
After long years of failure, the treatment of Alzheimer's disease through clearance of protein aggregates in the brain has been reinvigorated by minor degrees of success. The results are poor in the grand scheme of things, and come with risk of severe side-effects, but once a disease can be at least slowed, there is a renewed interest in improving on that starting point. It remains the case that the contributing causes of Alzheimer's disease remain poorly understood, however, and it may turn out to be much more preventable than thought. Assays to detect the earliest stages of the condition are now demonstrated, and promising work suggests that persistent viral infection may be an important factor that could be addressed via more widespread use of existing antiviral therapies.
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Amyloid-β (Aβ), tau, and neuroinflammation are immunotherapy targets focused on by industries for AD intervention. Passive immunotherapy targeting Aβ was launched decades ago and has reached milestone progress with full approval of lecanemab by the FDA very recently. While the development of monoclonal antibody (mAb) drugs targeting tau or immune modulators is at an early stage, several preclinical and clinical studies have shown promising results.
Here, we review characteristics, clinical trial data, and mechanisms of action for mAbs targeting key players in AD pathogenesis, including Aβ, tau, and neuroinflammation modulators. For the anti-Aβ strategy, it should be noted that even the mAbs (lecanemab and donanemab) only showed efficacy in patients with early AD. This may be because other factors, such as tau, have important contributions to neuronal loss in the later stages of AD. In support of this notion, donanemab only showed efficacy in AD patients with low/medium tau pathology.
Therefore, it is important to elucidate the clinical effect of anti-Aβ mAbs on neuronal loss, and it is worth testing the combined immunotherapy strategy targeting both Aβ and tau in patients with moderate symptoms or medium/severe tau pathology in the future. In addition, efficient Aβ-targeted immunotherapy is associated with a high incidence of ARIA and brain atrophy, and the underlying mechanisms need to be clarified. For anti-tau immunotherapy, most of the mAbs recognizing the N-terminal epitopes failed in clinical trials. The industries have now focused on developing mAbs targeting the tau mid-region or phosphorylated tau, which may be able to stop tau seeding and spreading.
https://www.sciencedirect.com/science/article/pii/S0361923022003264
Multiple roles of fucoxanthin and astaxanthin against Alzheimer's disease: Their pharmacological potential and therapeutic insights
https://doi.org/10.1016/j.brainresbull.2022.11.018
Alzheimer's disease is a neurodegenerative disorder that damages neurocognitive ability.
The major pathogenesis of Alzheimer's disease will be explained.
The therapeutic potentials of fucoxanthin and astaxanthin, as natural carotenoids present in algae, will be discussed.
Pharmacokinetics and pharmacodynamics properties of fucoxanthin and astaxanthin will be reviewed.
The new methodology to deliver fucoxanthin and astaxanthin to central nervous system will be explained.
Abstract
Alzheimer's disease (AD) is the most devastating neurodegenerative disorder affecting the elderly. The exact pathology of AD is not yet fully understood and several hallmarks such as the deposition of amyloid-β, tau hyperphosphorylation, and neuroinflammation, as well as mitochondrial, metal ions, autophagy, and cholinergic dysfunctions are known as pathologic features of AD. Since no definitive treatment has been proposed to target AD to date, many natural products have shown promising preventive potentials and contributed to slowing down the disease progression. Algae is a promising source of novel bioactive substances known to prevent neurodegenerative disorders including AD. In this context, fucoxanthin and astaxanthin, natural carotenoids abundant in algae, has shown to possess neuroprotective properties through antioxidant, and anti-inflammatory characteristics in modulating the symptoms of AD. Fucoxanthin and astaxanthin exhibit anti-AD activities by inhibition of AChE, BuChE, BACE-1, and MAO, suppression of Aβ accumulation. Also, fucoxanthin and astaxanthin inhibit apoptosis induced by Aβ1-42 and H2O2-induced cytotoxicity, and modulate the antioxidant enzymes (SOD and CAT), through inhibition of the ERK pathway. Moreover, cellular and animal studies on the beneficial effects of fucoxanthin and astaxanthin against AD were also reviewed. The potential role of fucoxanthin and astaxanthin exhibits great efficacy for the management of AD by acting on multiple targets.