Search for unknown neural link between the masticatory and cognitive brain systems to clarify the involvement of its impairment in the pathogenesis of Alzheimer's disease.

Brain degenerations in sporadic Alzheimer's disease (AD) are observed earliest in the locus coeruleus (LC), a population of noradrenergic neurons, in which hyperphosphorylated tau protein expression and ß-amyloid (Aß) accumulation begin. Along with this, similar changes occur in the basal forebrain cholinergic neurons, such as the nucleus basalis of Meynert. Neuronal degeneration of the two neuronal nuclei leads to a decrease in neurotrophic factors such as brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex, which results in the accumulation of Aß and hyperphosphorylated tau protein and ultimately causes neuronal cell death in those cortices. On the other hand, a large number of epidemiological studies have shown that tooth loss or masticatory dysfunction is a risk factor for dementia including AD, and numerous studies using experimental animals have also shown that masticatory dysfunction causes brain degeneration in the basal forebrain, hippocampus, and cerebral cortex similar to those observed in human AD, and that learning and memory functions are impaired accordingly. However, it remains unclear how masticatory dysfunction can induce such brain degeneration similar to AD, and the neural mechanism linking the trigeminal nervous system responsible for mastication and the cognitive and memory brain system remains unknown. In this review paper, we provide clues to the search for such "missing link" by discussing the embryological, anatomical, and physiological relationship between LC and its laterally adjoining mesencephalic trigeminal nucleus which plays a central role in the masticatory functions.

Dysfunction of norepinephrine and its metabolites in Alzheimer's dementia - A review with meta-analysis.

Some studies point locus coeruleus cell loss, the central nervous system main source of norepinephrine, to be one of the earliest neuropathological events of Alzheimer's disease (AD). However, there are conflicting reports regarding the level of norepinephrine and its metabolites (3-Methoxy-4-hydroxyphenylglycol (MHPG), 3,5-dihydroxyphenylglycine (DHPG) and 3,4 -dihydroxyphenylglycolaldehyde (DOPEGAL)) in AD patients. Uncover these alterations may be a key factor for understanding cognitive deficits and AD pathology. We review the literature that compare norepinephrine and its metabolites between AD patients and non-demented controls. A meta-analysis did not reveal significant statistical differences, but there was a trend towards a lower level of norepinephrine of AD, with almost no difference in MHPG in the cerebrospinal fluid. Regarding MHPG in plasma, DHPG and DOPEGAL we only performed a qualitative analyse due to the small or absent number of studies. These findings point to a decrease in norepinephrine, what is in line with locus coeluleus cell loss in AD. The absence of statistical difference and an equal level of MHGP could indicate a compensatory mechanism.

Oxidative Transformations of 3,4-Dihydroxyphenylacetaldehyde Generate Potential Reactive Intermediates as Causative Agents for Its Neurotoxicity.

Neurogenerative diseases, such as Parkinson's disease, are associated, not only with the selective loss of dopamine (DA), but also with the accumulation of reactive catechol-aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed as the immediate oxidation product of cytoplasmic DA by monoamine oxidase. DOPAL is well known to exhibit toxic effects on neuronal cells. Both catecholic and aldehyde groups seem to be associated with the neurotoxicity of DOPAL. However, the exact cause of toxicity caused by this compound remains unknown. Since the reactivity of DOPAL could be attributed to its immediate oxidation product, DOPAL-quinone, we examined the potential reactions of this toxic metabolite. The oxidation of DOPAL by mushroom tyrosinase at pH 5.3 produced conventional DOPAL-quinone, but oxidation at pH 7.4 produced the tautomeric quinone-methide, which gave rise to 3,4-dihydroxyphenylglycolaldehyde and 3,4-dihydroxybenzaldehyde as products through a series of reactions. When the oxidation reaction was performed in the presence of ascorbic acid, two additional products were detected, which were tentatively identified as the cyclized products, 5,6-dihydroxybenzofuran and 3,5,6-trihydroxybenzofuran. Physiological concentrations of Cu(II) ions could also cause the oxidation of DOPAL to DOPAL-quinone. DOPAL-quinone exhibited reactivity towards the cysteine residues of serum albumin. DOPAL-oligomer, the oxidation product of DOPAL, exhibited pro-oxidant activity oxidizing GSH to GSSG and producing hydrogen peroxide. These results indicate that DOPAL-quinone generates several toxic compounds that could augment the neurotoxicity of DOPAL.

ApoE4 inhibition of VMAT2 in the locus coeruleus exacerbates Tau pathology in Alzheimer's disease.

ApoE4 enhances Tau neurotoxicity and promotes the early onset of AD. Pretangle Tau in the noradrenergic locus coeruleus (LC) is the earliest detectable AD-like pathology in the human brain. However, a direct relationship between ApoE4 and Tau in the LC has not been identified. Here we show that ApoE4 selectively binds to the vesicular monoamine transporter 2 (VMAT2) and inhibits neurotransmitter uptake. The exclusion of norepinephrine (NE) from synaptic vesicles leads to its oxidation into the toxic metabolite 3,4-dihydroxyphenyl glycolaldehyde (DOPEGAL), which subsequently activates cleavage of Tau at N368 by asparagine endopeptidase (AEP) and triggers LC neurodegeneration. Our data reveal that ApoE4 boosts Tau neurotoxicity via VMAT2 inhibition, reduces hippocampal volume, and induces cognitive dysfunction in an AEP- and Tau N368-dependent manner, while conversely ApoE3 binds Tau and protects it from cleavage. Thus, ApoE4 exacerbates Tau neurotoxicity by increasing VMAT2 vesicle leakage and facilitating AEP-mediated Tau proteolytic cleavage in the LC via DOPEGAL.

Biogenic Aldehyde-Mediated Mechanisms of Toxicity in Neurodegenerative Disease.

Oxidative decomposition of several biomolecules produces reactive aldehydes. Monoamine neurotransmitters are enzymatically converted to aldehydes via monoamine oxidase followed by further metabolism such as carbonyl oxidation/reduction. Elevated levels of aldehyde intermediates are implicated as factors in several pathological conditions, including Parkinson's disease. The biogenic aldehydes produced from dopamine, norepinephrine and serotonin are known to be toxic, generate reactive oxygen species and/or cause aggregation of proteins such as α-synuclein. Polyunsaturated lipids undergo oxidative decomposition to produce biogenic aldehydes, including 4-hydroxy-2-nonenal and malondialdehyde. These lipid aldehydes, some including an α,ß-unsaturated carbonyl, target important proteins such as α-synuclein, proteasome degradation and G-protein-coupled signaling. Overproduction of biogenic aldehydes is a hypothesized factor in neurodegeneration; preventing their formation or scavenging may provide means for neuroprotection.

Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus.

Parkinson's disease (PD) is the most common neurodegenerative motor disease. Pathologically, PD is characterized by Lewy body deposition and subsequent death of dopamine neurons in the substantia nigra pars compacta. PD also consistently features degeneration of the locus ceruleus, the main source of norepinephrine in the central nervous system. We have previously reported a mouse model of dopaminergic neurodegeneration based on reduced expression of the vesicular monoamine transporter (VMAT2 LO). To determine if reduced vesicular storage can also cause noradrenergic degeneration, we examined indices of damage to the catecholaminergic systems in brain and cardiac tissue of VMAT2 LO mice. At two months of age, neurochemical analyses revealed substantial reductions in striatal dopamine (94%), cortical dopamine (57%) and norepinephrine (54%), as well as cardiac norepinephrine (97%). These losses were accompanied by increased conversion of dopamine and norepinephrine to their deaminated metabolites. VMAT2 LO mice exhibited loss of noradrenergic innervation in the cortex, as determined by norepinephrine transporter immunoreactivity and (3)H-nisoxetine binding. Using unbiased stereological techniques, we observed progressive degeneration in the locus ceruleus that preceded degeneration of the substantia nigra pars compacta. In contrast, the ventral tegmental area, which is spared in human PD, remained unaffected. The coordinate loss of dopamine and norepinephrine neurons in VMAT2 LO mice parallels the pattern of neurodegeneration that occurs in human PD, and demonstrates that insufficient catecholamine storage can cause spontaneous degeneration in susceptible neurons, underscoring cytosolic catecholamine catabolism as a determinant of neuronal susceptibility in PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.