No abstract

Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and -independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD.

Neurodegenerative disorders (NDs) are heterogeneous groups of ailments typically characterized by progressive damage of the nervous system. Several drugs are used to treat NDs but they have only symptomatic benefits with various side effects. Numerous researches have been performed to prove the advantages of phytochemicals for the treatment of NDs. Furthermore, phytochemicals such as polyphenols might play a pivotal role in rescue from neurodegeneration due to their various effects as anti-inflammatory, antioxidative, and antiamyloidogenic agents by controlling apoptotic factors, neurotrophic factors (NTFs), free radical scavenging system, and mitochondrial stress. On the other hand, neurotrophins (NTs) including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT4/5, and NT3 might have a crucial neuroprotective role, and their diminution triggers the development of the NDs. Polyphenols can interfere directly with intracellular signaling molecules to alter brain activity. Several natural products also improve the biosynthesis of endogenous genes encoding antiapoptotic Bcl-2 as well as NTFs such as glial cell and brain-derived NTFs. Various epidemiological studies have demonstrated that the initiation of these genes could play an essential role in the neuroprotective function of dietary compounds. Hence, targeting NTs might represent a promising approach for the management of NDs. In this review, we focus on the natural product-mediated neurotrophic signal-modulating cascades, which are involved in the neuroprotective effects.

Objectives Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders and a well-recognized cause of dementia with ageing. In this review, we have represented the ChE and MAO inhibitory potential of TV 3326 against AD based on current scientific evidence. Key findings The aetiology of AD is quite complex and not completely understood. However, it has been observed that AD involves the deposition of abnormal amyloid beta (Aβ), along with hyperphosphorylation of tau, oxidative stress, low acetylcholine (ACh) level and biometal dyshomeostasis. Due to the complex nature of AD aetiology, active research is required in the areas of development of multitarget drugs with 2 or more complementary biological functions, as they might represent significant progress in the AD treatment. Interestingly, it has been found that TV 3326 (i.e. ladostigil) is regarded as a novel therapeutic agent since it has the potential to cause inhibition of monoamine oxidase (MAO) A and B, and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain. Furthermore, it has the capacity to reverse memory impairments, which further suggests the ability of this drug to elevate cholinergic activity in the brain. Summary TV 3326 can avert oxidative–nitrative stress and gliosis. It has also been confirmed that TV 3326 contains neuroprotective and anti-apoptotic properties. Therefore, this distinctive combined inhibition of ChE and MAO along with its neuroprotective property makes TV 3326 a useful drug in the treatment of AD.