Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

Abstract

The incidence of metabolic disorders, as well as of neurodegenerative diseases-mainly the sporadic forms of Alzheimer's and Parkinson's disease-are increasing worldwide. Notably, obesity, diabetes, and hypercholesterolemia have been indicated as early risk factors for sporadic forms of Alzheimer's and Parkinson's disease. These conditions share a range of molecular and cellular features, including protein aggregation, oxidative stress, neuroinflammation, and blood-brain barrier dysfunction, all of which contribute to neuronal death and cognitive impairment. Rodent models of obesity, diabetes, and hypercholesterolemia exhibit all the hallmarks of these degenerative diseases, and represent an interesting approach to the study of the phenotypic features and pathogenic mechanisms of neurodegenerative disorders. We review the main pathological aspects of Alzheimer's and Parkinson's disease as summarized in rodent models of obesity, diabetes, and hypercholesterolemia.

Keywords: Alzheimer’s disease; Parkinson’s disease; diabetes; hypercholesterolemia; neurodegeneration; obesity; rodent models.

FIGURE 1

Neuropathological features of Alzheimer’s and Parkinson’s disease. The Alzheimer’s and Parkinson’s disease patients’ brains present neuronal dysfunction and loss, deposits of Aβ and α-synuclein protein, neuroinflammation (mainly characterized by microglia and astrocytes activation), and BBB leakage. Aβ, amyloid-β peptide; BBB, blood-brain barrier.

FIGURE 2

Brain alterations found in genetic mouse models of hypercholesterolemia. In LDLr^–/– and ApoE^–/– mice, both genetic mouse models of hypercholesterolemia, were observed increased levels of plasma cholesterol, BBB disruption, neuroinflammation, synaptic and neuronal dysfunction, impaired neurogenesis, and ultimately, cognitive impairments. ApoE^–/–, apolipoprotein E knockout mice; BBB, blood-brain barrier; LDLr^–/–, low-density lipoprotein receptor knockout mice.

FIGURE 3

High-fat diet exposure causes cerebral alterations associated with neurodegenerative diseases in mice. Mice fed a high-fat diet present increased Aβ levels, neuronal dysfunction and loss, BBB leakage, neuroinflammation, and, ultimately, cognitive and motor alterations. Aβ, amyloid-β peptide; BBB, blood-brain barrier.

FIGURE 4

Comparison between animal models of metabolic disorders, Alzheimer’s disease mouse model and Parkinson’s disease mouse model. The features of Alzheimer’s disease (A), including memory alterations, are also observed in hypercholesterolemic and obese rodents. The cognitive decline in obese and diet-induced hypercholesterolemic mice is associated with changes in Aβ levels, neuroinflammation, BBB dysfunction, and neuronal dysfunction, in the brain regions affected in Alzheimer’s disease. On the other hand, the genetic models of hypercholesterolemia also presented memory alterations, which are related to neurodegeneration, brain inflammation, BBB disruption, and neuronal dysfunction, but not modification in the Aβ deposits. Parkinson’s disease (B) features, including motor alterations, are also observed in hypercholesterolemic and obese rodents. Moreover, the hypercholesterolemic and 6-OHDA mouse model did not present an increase in α-synuclein mRNA expression while mice fed a high-fat diet presented. The motor alterations in obese, diet-induced hypercholesterolemic and 6-OHDA mice are associated with neuroinflammation, BBB dysfunction, and neuronal dysfunction in the brain regions affected by Parkinson’s disease. 6-OHDA, 6-hydroxydopamine; AD, Alzheimer disease; Aβ, amyloid-β peptide; BBB, blood-brain barrier; LDLr^–/–, low-density lipoprotein receptor knockout mice. (+) There is alteration, (–) there is no alteration.