Current Alzheimer Research - Volume 18, Issue 10, 2021

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will further increase with longer life expectancy. The AD brain is marked by severe neurodegeneration, such as the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems, especially in the hippocampus and cerebral cortex. Recent findings highlight the important role of mitochondrial dysfunction and increased oxidative stress in the pathophysiology of late-onset alzheimer’s disease (LOAD). These alterations are not only observed in the brain of AD patients but also in the periphery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells e.g. lymphocytes. We evaluate recent findings regarding impaired mitochondrial function comprising mitochondrial respiration, reduced complex activities of the respiratory chain and altered Mitochondrial Membrane Potential (MMP) in lymphocytes as well as in neurons. Finally, we will question whether these mitochondrial parameters might be suitable as an early peripheral marker for the detection of LOAD but also for the transitional stage between normal aging and Dementia, “Mild Cognitive Impairment” (MCI).

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments available for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initiation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mitochondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mitochondrial systems biology. We review evidence for mitochondrial impairments ranging from mitochondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expression, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dynamics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could potentially alter the course of this progressive, heterogeneous Disease while being cognizant that successful future therapeutics may require a combinatorial approach.

The Amyloid Precursor Protein (APP) is principally known and studied for its involvement in Alzheimer’s disease as the source of the amyloid β peptide; however, its physiological actions within the nervous system are also important as it is involved in a range of neuronal activities, including neurogenesis, synaptic plasticity, neurite outgrowth, and neuroprotection. Of the different neuronal functions that APP can affect, some may be relevant to APP’s role in Alzheimer’s disease, while others can be primarily related to its physiological roles. This review will focus on APP’s neuritogenic actions and surmise the key molecular mechanisms, as well as the structural and signaling requirements, which form the basis for APP’s neuritogenic effects. Deciphering the normal function(s) of APP is valuable to properly understanding its role in health as well as Alzheimer’s disease.

Alzheimer’s disease (AD) is characterized by progressive death of neuronal cells in the regions of the brain concerned with memory and cognition, and is the major cause of dementia in the elderly population. Various molecular mechanisms, metabolic risk factors and environmental triggers contributing to the genesis and progression of AD are under intense investigations. The present review has dealt with the impact of a highly discussed topic of gut microbiota affecting the neurodegeneration in the AD brain. A detailed description of the composition of gut bacterial flora and its interaction with the host has been presented, followed by an analysis of key concepts of bidirectional communication between gut microbiota and the brain. The substantial experimental evidence of gut microbiota affecting the neurodegenerative process in experimental AD models has been described next in this review, and finally, the limitations of such experimental studies vis-avis the actual disease and the paucity of clinical data on this topic have also been mentioned.

Alzheimer’s disease (AZD) is an age-associated neurodegenerative disorder and is one of the common health issues around the globe. It is characterized by memory loss and a decline in other cognitive domains, including executive function. The progression of AZD is associated with complex events, and the exact pathogenesis is still unrevealed. Various mechanisms which are thought to be associated with the initiation of AZD include a decreased concentration of acetylcholine (ACh), deposition of amyloid-β (Aβ) peptide, dyshomeostasis of redox metal ions, and prolonged oxidative stress. Due to the simultaneous progression of diverse pathogenetic pathways, no ideal therapeutic agent has been developed to date. The drugs which are available against AZD provide only symptomatic benefits and do not have disease-modifying activity. Therefore, in search of ideal therapeutic candidates, the concept of molecular hybrids has been under keen investigation for the past few years. Hybrid molecules are able to inhibit or activate or modify the physiology of more than one target simultaneously. Coumarin scaffold have shown the excellent potential of ACh esterase inhibition, MAO-B inhibition, and anti-Aβ aggregation. In the present review, we have focused on different reported coumarin hybrids as multi-target-directed agents against AZD. These include hybrids of coumarin with carbazole, benzofuran, dithiocarbamate, quinoline, pargyline, tacrine, N-benzyl pyridinium, donepezil, purine, piperidine, morpholine, aminophenol, benzylamino, halophenylalkylamidic, thiazole, thiourea, hydroxypyridinone, triazole, piperazine, chalcone, etc. Along with the therapeutic potentials of these hybrids, important clinical investigations and the structure-activity relationship have also been discussed in this compilation.

Nitric oxide synthase (NOS) is well known for its involvement in the regulation of the nervous, cardiovascular, and immune systems. Neuronal NOS (nNOS) is the most characterized NOS among all the isoforms. It accounts for most of the production of nitric oxide (NO) in the nervous system required for synaptic transmission and neuroplasticity. Previous studies have described the localization of nNOS in specific brain regions of interest. There is substantial evidence in the literature suggesting that nNOS signaling has significant involvement in several disease pathologies. However, the association between brain nNOS expression profiles and disease remains largely unknown. In this review, we attempt to delineate the contribution of nNOS signaling in memory and mood disorders in order to achieve a better understanding of nNOS in disease modulation.

Neuroscience has long sought to develop methods that can “edit” or even “erase” memories, with the aim to provide treatments for memory-related neurological and psychiatric diseases such as anxiety and addiction. Current efforts are heavily focused on modifying cognitive behavioral therapy protocols or pharmacological treatments, but the efficacy and safety of these methods have been called into question by several studies. Advances in modern technology and the rapid emergence of techniques that can directly stimulate/alter neuronal activity, such as neuromodulation, have great potential in achieving the goal of memory modification for treating dementia such as Alzheimer’s disease. However, more research and validation studies are required before these memory editing technologies can be applied clinically. In this mini-review, we compare and highlight the advantages and disadvantages of cognitive behavioral therapy, pharmacological methods, and neuromodulation techniques. We believe that neuromodulation techniques will play a key role in overcoming the challenges of translating memory-manipulating techniques to clinical applications.