Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation.

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.

The structure of neuromelanin and its iron binding site studied by infrared spectroscopy.

The binding of neuromelanin (NM) to iron is of interest due to its role in brain aging and Parkinson's disease. In the present work, infrared spectra of both NM isolated from huma brain and of synthetic NM analogues are reported with the aim of identifying the main functional groups and their chelating ability for iron. It is observed that a peptide and an aliphatic chain are present in the NM structure. The coordination of iron in NM occurs through -OH phenolic units. In synthetic melanin samples, the preferred sites for iron binding are -OH phenolic and [symbol: see text]NH indolic groups. Amino acid analysis confirmed the presence of a peptide component in NM and synthetic melanin incubated in putamen homogenate. In addition, the elemental analysis demonstrated the presence of an aliphatic component specific of NM.

The neuromelanin of human substantia nigra: structure, synthesis and molecular behaviour.

The pigmented neurons of the substantia nigra (SN) are typically lost in Parkinson's disease: however the possible relationship between neuronal vulnerability and the presence of neuromelanin (NM) has not been elucidated. Early histological studies revealed the presence of increasing amounts of NM in the SN with aging in higher mammals, showed that NM granules are surrounded by membrane, and comparatively evaluated the pigmentation of SN in different animal species. Histochemical studies showed the association of NM with lipofuscins. However, systematic investigations of NM structure, synthesis and molecular interactions have been undertaken only during the last decade. In these latter studies, NM was identified as a genuine melanin with a strong chelating ability for iron and affinity for compounds such as lipids, pesticides, and MPP+. The affinity of NM for a variety of inorganic and organic toxins is consistent with a postulated protective function for NM. Moreover, the neuronal accumulation of NM during aging, and the link between its synthesis and high cytosolic concentration of catechols suggests a protective role. However, its putative neuroprotective effects could be quenched in conditions of toxin overload.

Substantia nigra neuromelanin: structure, synthesis, and molecular behaviour.

The pigmented neurones of the substantia nigra are typically lost in Parkinson's disease; however, the possible relation between neuronal vulnerability and the presence of neuromelanin has not been elucidated. Early histological studies revealed the presence of increasing amounts of neuromelanin in the substantia nigra with aging in higher mammals, showed that the neuromelanin granules are surrounded by a membrane, and comparatively evaluated the pigmentation of the substantia nigra in different animal species. Histochemical studies showed the association of neuromelanin with lipofuscins. However, systematic investigations of the structure, synthesis, and molecular interactions of neuromelanin have been undertaken only during the past decade. In these later studies, neuromelanin was identified as a genuine melanin with a strong chelating ability for iron and an affinity for compounds such as lipids, pesticides, and MPP(+). The affinity of neuromelanin for a variety of inorganic and organic toxins is consistent with a postulated protective function for neuromelanin. Moreover, the neuronal accumulation of neuromelanin during aging and the link between its synthesis and a high cytosolic concentration of catechols suggest a protective role. However, its putative neuroprotective effects could be quenched in conditions of toxin overload.

Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: consequences for iron storage and neurodegenerative processes.

Information on the molecular distribution and ageing trend of brain iron in post-mortem material from normal subjects is scarce. Because it is known that neuromelanin and ferritin form stable complexes with iron(III), in this study we measured the concentration of iron, ferritin and neuromelanin in substantia nigra from normal subjects, aged between 1 and 90 years, dissected post mortem. Iron levels in substantia nigra were 20 ng/mg in the first year of life, had increased to 200 ng/mg by the fourth decade and remained stable until 90 years of age. The H-ferritin concentration was also very low (29 ng/mg) during the first year of life but increased rapidly to values of approximately 200 ng/mg at 20 years of age, which then remained constant until the eighth decade of life. L-Ferritin also showed an increasing trend during life although the concentrations were approximately 50% less than that of H-ferritin at each age point. Neuromelanin was not detectable during the first year, increased to approximately 1000 ng/mg in the second decade and then increased continuously to 3500 ng/mg in the 80th year. A Mössbauer study revealed that the high-spin trivalent iron is probably arranged in a ferritin-like iron--oxyhydroxide cluster form in the substantia nigra. Based on this data and on the low H- and L-ferritin content in neurones it is concluded that neuromelanin is the major iron storage in substantia nigra neurones in normal individuals.

The neuromelanin of human substantia nigra and its interaction with metals.

Neuromelanin (NM) is a peculiar biochemical component of several neurons in the Substantia Nigra (SN), the target area of the degenerative process in Parkinson Disease (PD). SN NM has peculiarities as to its composition and an impressive capacity of chelating metals, iron in particular, but not exclusively. Gaining insights into the structural and functional characteristics of NM should help understanding the reasons of selective vulnerability of nigral neurons in many parkinsonian conditions. From the present data a protective role of NM can be postulated until the buffering capability toward heavy metals are exhausted. The overloading of NM with iron and other metals in neurons may trigger inflammatory and degenerative processes aggravating the underlying pathological condition.