The term oligomeropathies defines the neurodegenerative disorders associated with protein misfolding, where small soluble aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathology. The ability of these soluble β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides. Together with the neuronal death, synaptic dysfunction, loss of spines, and LTP impairment were seen with the direct application of β amyloid oligomers. Similar results have been described with proteins associated with other neurodegenerative disorders. The biological activities of oligomeric forms of α synuclein have been described in Parkinson's disease and Lewy body dementia. Detrimental effects have been associated with the oligomeric forms of prion, tau, and huntingtin, the key proteins in prion diseases, frontotemporal dementia, and Huntington's disease, respectively. The molecular mechanisms of the oligomer-related toxic effects can be summarized under three headings: nonspecific perturbance of cellular and intracellular membranes, specific interaction with various cellular entities, and amyloid pore channel formation. To characterize and distinguish oligomer actions better, we compared the ability of β amyloid and α synuclein oligomers to induce cognitive impairment when applied directly into the brain in the same acute mouse model. We also investigated the role of inflammatory components. © 2016 International Parkinson and Movement Disorder Society.

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Mechanisms of tissue damage in Huntington's disease involve excitotoxicity, mitochondrial damage, and inflammation, including microglia activation. Immunomodulatory and anti-protein aggregation properties of tetracyclines were demonstrated in several disease models. In the present study, the neuroprotective and anti-inflammatory effects of the tetracycline doxycycline were investigated in the mouse model of HD disease R6/2. Transgenic mice were daily treated with doxycycline 20 mg/kg, starting from 4 weeks of age. After sacrifice, histological and immunohistochemical studies were performed. We found that doxycycline-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the saline-treated ones. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and the negative modulation of microglial reaction revealed a neuroprotective effect of the compound. Doxycycline provided a significantly increase of activated CREB and BDNF in the striatal neurons, along with a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings show that doxycycline treatment could be considered as a valid therapeutic approach for HD.

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In the last two decades, knowledge of the neurobiology of prion diseases or transmissible spongiform encephalopathies (TSE) has significantly advanced, but a successful therapy to stop or delay the progression of these disorders remains one of the most challenging goals of biomedical research. Several obstacles to this achievement are in common with other neurodegenerative disorders: difficulties to move from experimental level to clinical stage; appropriate timing of intervention; correct set up of clinical trial. Also in terms of molecular bases of disease, TSE and the other neurodegenerative disorders associated with protein misfolding such as Alzheimer, Parkinson and Huntington diseases, share a central pathogenic role of soluble small aggregates, named oligomers, considered the culprit of neuronal dysfunction: accordingly, these disorders could by termed oligomeropathies. However, the rapid progression of TSE, together with their clinical and molecular heterogeneity, make the therapeutic approach particularly problematic. The main target of the antiprion strategy has been the pathological form of the cellular prion protein (PrP(C)) termed PrP(Sc), invariably associated with the diseases. Several compounds have been found to affect PrP(Sc) formation or enhance its clearance in in vitro models, and prolong survival in experimental animals. However, few of them such as quinacrine and pentosan polysulfate have reached the clinical evaluation; more recently, we have conducted a clinical trial with doxycycline in patients with Creutzfeldt-Jakob disease without satisfactory results. In experimental conditions, active and passive immunization with antibodies against PrP and mucosal vaccination have shown to protect from peripheral infection. Other studies have proposed new potentially effective molecules targeting PrP oligomers. Furthermore, the possibility to interfere with PrP(C) to PrP(Sc) conversion by an active control of PrP(C) is another interesting approach emerging from experimental studies. However, in common with the other oligomeropathies, early diagnosis allowing to treat at risk population in a preclinical stage represent the more realistic perspective for efficient TSE therapy.