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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.

SUBMITTER: Vidal C

PROVIDER: S-EPMC7998384 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Amyloid deposition and neurofibrillary degeneration in Alzheimer's disease specifically affect discrete neuronal systems, but the underlying mechanisms that render some brain regions more vulnerable to Alzheimer's disease pathology than others remain largely unknown. Here we studied molecular properties underlying these distinct regional vulnerabilities by analysing Alzheimer's disease-typical neuroimaging patterns of amyloid deposition and neurodegeneration in relation to regional gene expression profiles of the human brain. Graded patterns of brain-wide vulnerability to amyloid deposition and neurodegeneration in Alzheimer's disease were estimated by contrasting multimodal amyloid-sensitive PET and structural MRI data between patients with Alzheimer's disease dementia (n = 76) and healthy controls (n = 126) enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Regional gene expression profiles were derived from brain-wide microarray measurements provided by the Allen brain atlas of the adult human brain transcriptome. In a hypothesis-driven analysis focusing on the genes coding for the amyloid precursor (APP) and tau proteins (MAPT), regional expression levels of APP were positively correlated with the severity of regional amyloid deposition (r = 0.44, P = 0.009), but not neurodegeneration (r = 0.01, P = 0.96), whereas the opposite pattern was observed for MAPT (neurodegeneration: r = 0.46, P = 0.006; amyloid: r = 0.08, P = 0.65). Using explorative gene set enrichment analysis, amyloid-vulnerable regions were found to be characterized by relatively low expression levels of gene sets implicated in protein synthesis and mitochondrial respiration. By contrast, neurodegeneration-vulnerable regions were characterized by relatively high expression levels of gene sets broadly implicated in neural plasticity, with biological functions ranging from neurite outgrowth and synaptic contact over intracellular signalling cascades to proteoglycan metabolism. At the individual gene level this data-driven analysis further corroborated the association between neurodegeneration and MAPT expression, and additionally identified associations with known tau kinases (CDK5, MAPK1/ERK2) alongside components of their intracellular (Ras-ERK) activation pathways. Sensitivity analyses showed that these pathology-specific imaging-genetic associations were largely robust against changes in some of the methodological parameters, including variation in the brain donor sample used for estimating regional gene expression profiles, and local variations in the Alzheimer's disease-typical imaging patterns when these were derived from an independent patient cohort (BioFINDER study). These findings highlight that the regionally selective vulnerability to Alzheimer's disease pathology relates to specific molecular-functional properties of the affected neural systems, and that the implicated biochemical pathways largely differ for amyloid accumulation versus neurodegeneration. The data provide novel insights into the complex pathophysiological mechanisms of Alzheimer's disease and point to pathology-specific treatment targets that warrant further exploration in independent studies.

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

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