Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson's disease.

The pathological misfolding and aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, a progressive age-related neurodegenerative disease for which there is no cure. HET-s is a soluble fungal protein that can form assembled amyloid fibrils in its prion state. We engineered HET-s(218-298) to form four different fibrillar vaccine candidates, each displaying a specific conformational epitope present on the surface of α-synuclein fibrils. Vaccination with these four vaccine candidates prolonged the survival of immunized TgM83+/- mice challenged with α-synuclein fibrils by 8% when injected into the brain to model brain-first Parkinson's disease or by 21% and 22% when injected into the peritoneum or gut wall, respectively, to model body-first Parkinson's disease. Antibodies from fully immunized mice recognized α-synuclein fibrils and brain homogenates from patients with Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Conformation-specific vaccines that mimic epitopes present only on the surface of pathological fibrils but not on soluble monomers, hold great promise for protection against Parkinson's disease, related synucleinopathies and other amyloidogenic protein misfolding disorders.

Ischemic stroke causes Parkinson's disease-like pathology and symptoms in transgenic mice overexpressing alpha-synuclein.

The etiology of Parkinson's disease is poorly understood and is most commonly associated with advancing age, genetic predisposition, or environmental toxins. Epidemiological findings suggest that patients have a higher risk of developing Parkinson's disease after ischemic stroke, but this potential causality lacks mechanistic evidence. We investigated the long-term effects of ischemic stroke on pathogenesis in hemizygous TgM83 mice, which express human α-synuclein with the familial A53T mutation without developing any neuropathology or signs of neurologic disease for more than 600 days. We induced transient focal ischemia by middle cerebral artery occlusion in 2-month-old TgM83+/- mice and monitored their behavior and health status for up to 360 days post surgery. Groups of mice were sacrificed at 14, 30, 90, 180, and 360 days after surgery for neuropathological analysis of their brains. Motor deficits first appeared 6 months after focal ischemia and worsened until 12 months afterward. Immunohistochemical analysis revealed ischemia-induced neuronal loss in the infarct region and astrogliosis and microgliosis indicative of an inflammatory response, which was most pronounced at 14 days post surgery. Infarct volume and inflammation gradually decreased in size and severity until 180 days post surgery. Surprisingly, neuronal loss and inflammation were increased again by 360 days post surgery. These changes were accompanied by a continuous increase in α-synuclein aggregation, its neuronal deposition, and a late loss of dopaminergic neurons in the substantia nigra, which we detected at 360 days post surgery. Control animals that underwent sham surgery without middle cerebral artery occlusion showed no signs of disease or neuropathology. Our results establish a mechanistic link between ischemic stroke and Parkinson's disease and provide an animal model for studying possible interventions.

Olfactory stimulation Inhibits Nociceptive Signal Processing at the Input Stage of the Central Trigeminal System.

The spinal trigeminal nucleus caudalis (SpVc) in the mammalian brainstem serves a pivotal function in pain processing. As the main relay center for nociceptive signals, SpVc conducts pain-related signals from various regions of the head toward higher levels of central processing such as the thalamus. SpVc also receives modulatory signals from other brain areas, which can alleviate the perception of headache. We studied the impact of olfactory co-stimulation on pain-related behavior and SpVc neural activity in mice. Using the TRPA1 agonist allyl isothiocyanate (AITC) as noxious stimulus, we quantified the aversive response and the perceived pain intensity by evaluating explorative running and the mouse grimace scale, respectively. We found that the floral odorants phenylethyl alcohol (PEA) and lavender oil mitigated the aversive response to AITC. Consistent with this finding, a newly developed, automated quantification of c-Fos expression in SpVc revealed that co-stimulation with PEA or lavender profoundly reduced network activity in the presence of AITC. These results demonstrated a substantial analgesic potential of odor stimulation in the trigeminal system and provide an explanation for the palliative effect of odors in the treatment of headache.

Pavlovian to Instrumental Transfer Responses Do Not Correlate With Addiction-Like Behavior in Rats.

Pavlovian learning plays a prominent role in the etiology of addiction. The influence of Pavlovian conditioning on the expression of an instrumental response can be studied using the Pavlovian-to-instrumental transfer (PIT) paradigm. This paradigm consists of independent Pavlovian conditioning and instrumental training prior to the combination of both during the test. During this test, the reward is not available, and an increase in the instrumental responding during conditioned stimuli presentation is a measure of PIT. Recent studies have reported a higher PIT in alcohol and nicotine dependent patients, suggesting that enhanced PIT might be a marker for dependence vulnerability. However, these studies did not use standard PIT procedures, and a clear correlation between an enhanced PIT and drug-related and addictive behaviors has so far not been demonstrated. For a systematic evaluation rats were trained in a cocaine addiction model. Addicted-like and non-addicted-like rats were subsequently assessed in the PIT paradigm. In a further experiment, rats were first tested in the PIT paradigm and thereafter subjected to cocaine self-administration (CSA) training. Our results revealed that addicted-like rats did not differ from non-addicted-like in their performance in the PIT test. However, CSA behavior showed a positive correlation with PIT. This data suggests that stronger PIT may predict higher motivational impact of conditioned stimuli on drug self-administration and improved learning of drug-cue association rather than the risk to develop addiction as such.