Neurochemical Research

, Volume 37, Issue 4, pp 846–868

Dysfunctional Nucleus Tractus Solitarius: Its Crucial Role in Promoting Neuropathogentic Cascade of Alzheimer’s Dementia—A Novel Hypothesis

Overview

DOI: 10.1007/s11064-011-0680-2

Cite this article as:
Daulatzai, M.A. Neurochem Res (2012) 37: 846. doi:10.1007/s11064-011-0680-2

Abstract

The pathophysiological mechanism(s) underlying Alzheimer’s disease (AD) still remain unclear, and no disease-modifying or prophylactic therapies are currently available. Unraveling the fundamental neuropathogenesis of AD is an important challenge. Several studies on AD have suggested lesions in a number of CNS areas including the basal forebrain, hippocampus, entorhinal cortex, amygdale/insula, and the locus coeruleus. However, plausible unifying studies on the upstream factors that involve these heterogeneous regions and herald the onset of AD pathogenesis are not available. The current article presents a novel nucleus tractus solitarius (NTS) vector hypothesis that underpins several disparate biological mechanisms and neural circuits, and identifies relevant hallmarks of major presumptive causative factor(s) linked to the NTS, in older/aging individuals. Aging, obesity, infection, sleep apnea, smoking, neuropsychological states, and hypothermia—all activate inflammatory cytokines and oxidative stress. The synergistic impact of systemic proinflammatory mediators activates microglia and promotes neuroinflammation. Acutely, the innate immune response is protective defending against pathogens/toxins; however, when chronic, it causes neuroinflammation and neuronal dysfunction, particularly in brainstem and neocortex. The NTS in the brainstem is an essential multiple signaling hub, and an extremely important central integration site of baroreceptor, chemoreceptor, and a multitude of sensory afferents from gustatory, gastrointestinal, cardiac, pulmonary, and upper airway systems. Owing to persistent neuroinflammation, the dysfunctional NTS exerts deleterious impact on nucleus ambiguus, dorsal motor nucleus of vagus, hypoglossal, parabrachial, locus coeruleus and many key nuclei in the brainstem, and the hippocampus, entorhinal cortex, prefrontal cortex, amygdala, insula, and basal forebrain in the neocortex. The neuronal and synaptic dysfunction emanating from the inflamed NTS may affect its interconnected pathways impacting almost the entire CNS—which is already primed by neuroinflammation, thus promoting cognitive and neuropsychiatric symptoms. The upstream factors discussed here may underpin the neuropathopgenesis of AD. AD pathology is multifactorial; the current perspective underscores the value of attenuating disparate upstream factors—in conjunction with anticholinesterase, anti-inflammatory, immunosuppressive, and anti-oxidant pharmacotherapy. Amelioration of the NTS pathology may be of central importance in countering the neuropathological cascade of AD. The NTS, therefore, may be a potential target of novel therapeutic strategies.

Keywords

Alzheimer’s disease Neuroinflammation Nucleus tractus solitarius Hypoglossal Vagus nerve Sleep apnea 

Abbreviations

α1-ACT

α1-Antichymotrypsin

Amyloid beta

Ach

Acetylcholine

BFB

Basal forebrain

BP

Blood pressure

AD

Alzheimer’s disease

AHI

Apnea hypopnea index

AP

Area postrema

APR

Acute phase response

BFB

Basal forebrain

BMI

Basal metabolic index

BBB

Blood brain barrier

CBF

Cerebral blood flow

CCL2

Chemokine ligand 2

CD15

Immunological carbohydrate adhesion molecule

CIC

Circulating inflammatory cytokines,

c-fos

Proto-oncogene

CIM

Circulating inflammatory mediators

CNS

Central nervous system

COX-2

Cyclooxygenase-2

CRP

C-reactive protein

DMNV

Dorsal motor nucleus of the vagus nerve

DVC

Dorsal vagal complex

ERC

Entorhinal cortex

GMV

Gray matter volume

HIF-1

Hypoxia-inducible factor 1

ICAM 1

Intercellular adhesion molecule 1

IFNγ

Interferon gamma

IL

Interleukin

LPS

Lipopolysaccharide

MCI

Mild cognitive impairment

MIP-2

Macrophage inflammatory protein

NA

Nucleus ambiguus

NF-κB

Nuclear factor of kappa light polypeptide gene enhancer in B-cells

NTS

Nucleus tractus solitarius

NO

Nitric oxide

NOS

Nitric oxide synthase

NK

Natural killer cell

OB

Olfactory bulb

OFC

Orbitofrontal cortex

ON

Olfactory nerve

OSA

Obstructive sleep apnea

PC

Piriform cortex

PFC

Prefrontal cortex

p-tau

Hyperphosphorylated tau

ROS

Reactive oxygen species

TGF-β

Transforming growth factor beta

THP-1

Human acute monocytic leukemia cell line

TNF

Tumor necrosis factor

VCAM-1

Vascular cell adhesion molecule-1

VNS

Vagus nerve stimulation

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Sleep Disorders Group, EEE Department, MSEUniversity of MelbourneParkvilleAustralia