A Bird’s-Eye View of the Multiple Biochemical Mechanisms that Propel Pathology of Alzheimer’s Disease: Recent Advances and Mechanistic Perspectives on How to Halt the Disease Progression Targeting Multiple Pathways

Abstract

Neurons consume the highest amount of oxygen, depend on oxidative metabolism for energy, and survive for the lifetime of an individual. Therefore, neurons are vulnerable to death caused by oxidative-stress, accumulation of damaged and dysfunctional proteins and organelles. There is an exponential increase in the number of patients diagnosed with neurodegenerative diseases such as Alzheimer's (AD) as the number of elderly increases exponentially. Development of AD pathology is a complex phenomenon characterized by neuronal death, accumulation of extracellular amyloid-␤ plaques and neurofibrillary tangles, and most importantly loss of memory and cognition. These pathologies are most likely caused by mechanisms including oxidative stress, mitochondrial dysfunction/stress, accumulation of misfolded proteins, and defective organelles due to impaired proteasome and autophagy mechanisms. Currently, there are no effective treatments to halt the progression of this disease. In order to treat this complex disease with multiple biochemical pathways involved, a complex treatment regimen targeting different mechanisms should be investigated. Furthermore, as AD is a progressive disease-causing morbidity over many years, any chemo-modulator for treatment must be used over long period of time. Therefore, treatments must be safe and non-interfering with other processes. Ideally, a treatment like medicinal food or a supplement that can be taken regularly without any side effect capable of reducing oxidative stress, stabilizing mitochondria, activating autophagy or proteasome, and increasing energy levels of neurons would be the best solution. This review summarizes progress in research on different mechanisms of AD development and some of the potential therapeutic development strategies targeting the aforementioned pathologies.

Combined Ubisol-Q10 and Ashwagandha Root Extract Target Multiple Biochemical Mechanisms and Reduces Neurodegeneration in a Paraquat-Induced Rat Model of Parkinson’s Disease

“…Although not directly pertaining to PD, AD shares the same biochemical mechanisms (oxidative stress, mitochondrial dysfunction, impaired autophagy, and neuroinflammation) [39]. While Ubisol-Q 10 seems like a promising therapeutic, it does not target all biochemical mechanisms of PD.…”

Resumption of Autophagy by Ubisol-Q10 in Presenilin-1 Mutated Fibroblasts and Transgenic AD Mice: Implications for Inhibition of Senescence and Neuroprotection

“…Under these circumstances, defective/misfolded toxic proteins such as βamyloid and dysfunctional organelles such as mitochondria can accumulate causing stress on cells leading to eventual cell death. Excessive oxidative stress can also affect various autophagy regulators such as beclin-1 (a major regulator of autophagosome maturation) [24]. Furthermore, PS-1 mutations have been shown to inhibit autophagy progression via blocking autophagosome maturation [25].…”

Flavonoid-Based Nanomedicines in Alzheimer’s Disease Therapeutics: Promises Made, a Long Way To Go

“…20 As a plethora of changes in the aging brain may lead to multiple pathologies, an ideal chemotherapeutic agent is required to be particularly effective for blocking multiple pathways leading to AD development. 21 Compounds with multitudinous biological activities, e.g., flavonoids, can possibly affect various age-associated changes in the human brain, which otherwise may contribute to disease development and progression. 22 A recent study examining the relationship between intake of flavonoids and risk of AD provides convincing pieces of evidence that long-term intakes of a flavonoid-rich diet are associated with reduced risks of developing AD.…”