An Analysis of the Neurological and Molecular Alterations Underlying the Pathogenesis of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid beta (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Unfortunately, despite decades of studies being performed on these histological alterations, there is no effective treatment or cure for AD. Identifying the molecular characteristics of the disease is imperative to understanding the pathogenesis of AD. Furthermore, uncovering the key causative alterations of AD can be valuable in developing models for AD treatment. Several alterations have been implicated in driving this disease, including blood–brain barrier dysfunction, hypoxia, mitochondrial dysfunction, oxidative stress, glucose hypometabolism, and altered heme homeostasis. Although these alterations have all been associated with the progression of AD, the root cause of AD has not been identified. Intriguingly, recent studies have pinpointed dysfunctional heme metabolism as a culprit of the development of AD. Heme has been shown to be central in neuronal function, mitochondrial respiration, and oxidative stress. Therefore, dysregulation of heme homeostasis may play a pivotal role in the manifestation of AD and its various alterations. This review will discuss the most common neurological and molecular alterations associated with AD and point out the critical role heme plays in the development of this disease.

Neuroinflammation in Alzheimer’s Disease

“…Both share almost similar pathophysiology [ 44 , 45 ]. Three causative genes, including presenilin 1 (PSEN1) [ 46 ], presenilin 2 (PSEN2) [ 47 ], and amyloid precursor protein (APP) [ 48 ], are involved in the pathogenesis of EOAD in an autosomal-dominant trait [ 49 , 50 ]. LOAD, however, comprises most AD cases (>95%) where the greatest risk factor is advanced age [ 51 ], while the common genetic risk factor is an allelic variation in apolipoprotein E (Apo E) [ 52 ].…”

Interaction Interface of Aβ42 with Human Na,K-ATPase Studied by MD and ITC and Inhibitor Screening by MD

“…Posttranslational modifications of the Aβ 42 peptide, especially Asp7 isomerization and Ser8 phosphorylation, affect its oligomerization and neurotoxic effect [ 6 , 7 , 8 , 9 , 10 ]. At the same time, Aβ is a regulatory peptide that interacts with different target proteins in a healthy organism, and during AD is involved in pathogenic reactions that result in neurotoxic effects and neurodegeneration in brains of AD patients [ 11 , 12 , 13 ]. Some researchers insist on the primary role of pathogenic cascades induced by Aβ interaction with its targets (receptors) in AD severity [ 11 , 13 ].…”

“…At the same time, Aβ is a regulatory peptide that interacts with different target proteins in a healthy organism, and during AD is involved in pathogenic reactions that result in neurotoxic effects and neurodegeneration in brains of AD patients [ 11 , 12 , 13 ]. Some researchers insist on the primary role of pathogenic cascades induced by Aβ interaction with its targets (receptors) in AD severity [ 11 , 13 ]. There is evidence that Aβ binds to postsynaptic receptors, such as α7-nicotinic acetylcholine (α7nAChR) [ 14 ] and α4β2-nicotinic acetylcholine (α4β2 nAChR) [ 15 ], receptors for advanced glycation end products (RAGE) [ 16 ], NLRP3 inflammasome [ 17 ], Na,K-ATPase [ 18 ] and others.…”

Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease

“…Initially, the β-APP-site cleaving enzyme (BACE), a membrane-bound aspartyl protease, cleaves APP, generating a secreted APP derivative, sAPP, and the membrane-bound protein β-secretase-derived C-terminal fragment (CTFβ). Later, CTFβ is cleaved by γ-secretase, producing different lengths of Aβ, which are released into the extracellular space, and an APP intracellular domain (AICD) released to the cytoplasm [ 386 , 387 ]. Aβ 40 is the most abundant form of Aβ produced into the cells.…”