Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration

Abstract

Alzheimer's disease (AD) is a complex, multifactorial disease with a number of leading mechanisms, including neuroinflammation, processing of amyloid precursor protein (APP) to amyloid β peptide, tau protein hyperphosphorylation, relocalization, and deposition. These mechanisms are propagated by obesity, the metabolic syndrome and type-2 diabetes mellitus. Stress, sedentariness, dietary overconsumption of saturated fat and refined sugars, and circadian derangements/disturbed sleep contribute to obesity and related metabolic diseases, but also accelerate age-related damage and senescence that all feed the risk of developing AD too. The complex and interacting mechanisms are not yet completely understood and will require further analysis. Instead of investigating AD as a mono- or oligocausal disease we should address the disease by understanding the multiple underlying mechanisms and how these interact. Future research therefore might concentrate on integrating these by "systems biology" approaches, but also to regard them from an evolutionary medicine point of view. The current review addresses several of these interacting mechanisms in animal models and compares them with clinical data giving an overview about our current knowledge and puts them into an integrated framework.

Keywords: Alzheimer's disease; TNF; aging; blood-brain barrier; metabolic syndrome; neuroinflammation; obesity; type-2 diabetes mellitus.

Figure 1

Detrimental and healthy life style factors respectively stimulate and reduce the risk for attracting obesity, the metabolic syndrome and type-2 diabetes mellitus. These factors also have a stimulatory effect per sé on age-related damage and accelerate senescence. Associated with obesity, metabolic syndrome, and type-2 diabetes mellitus, there is inflammation, insulin resistance, and hyperinsulinemia (i.e., depending on the stage of type-2 diabetes mellitus). Hyperactivity of the sympathetic nervous system and HPA axis worsen insulin resistance and deteriorate cardiovascular health. At the level of the brain, several mechanisms are set in place, among which neuroinflammation and insufficient brain fueling are proposed to backfire and contribute to increased sympathetic and HPA activity as well. Finally, these processes lead up to Aβ aggregation, Tau hyperphosphorylation, and NeuroFibrillary Tangle (NFT) deposition, which also backfire and culminate into AD. (1) Upregulating ketone provision to the brain, (2) exercise/physical activity, and (3) increasing the level of n-3 PUFAs (by diet supplementation as preventive action) slow the progressive stages in the disease, and are also proposed to reduce the backfiring effects, which puts a brake on the vicious cycles in the etiology of AD.