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Peroxisome proliferator-activated receptors (PPARs) control the expression of genes involved in glucose homeostasis, lipid metabolism, inflammation, and cell differentiation. Here, we analyzed the effects of aleglitazar, a dual PPARα and PPARγ agonist with balanced affinity for either subtype, on subacute stroke outcome. Healthy young adult mice were subjected to transient 30 min middle cerebral artery occlusion (MCAo)/reperfusion. Daily treatment with aleglitazar was begun on the day of MCAo and continued until sacrifice. Blood glucose measurements and lipid profile did not differ between mice receiving aleglitazar and mice receiving vehicle after MCAo. Aleglitazar reduced the size of the ischemic lesion as assessed using NeuN immunohistochemistry on day 7. Sensorimotor performance on the rotarod was impaired during the first week after MCAo, an effect that was significantly attenuated by treatment with aleglitazar. Smaller lesion volume in mice treated with aleglitazar was accompanied by a decrease in mRNA transcription of IL-1β, Vcam-1, and Icam-1, suggesting that reduced proinflammatory signaling and reduced vascular inflammation in the ischemic hemisphere contribute to the beneficial effects of aleglitazar during the first week after stroke. Further experiments in primary murine microglia confirmed that aleglitazar reduces key aspects of microglia activation including NO production, release of proinflammatory cytokines, migration, and phagocytosis. In aggregate, a brief course of PPARα/γ agonist aleglitazar initiated post-event affords stroke protection and functional recovery in a model of mild brain ischemia. Our data underscores the theme of delayed injury processes such as neuroinflammation as promising therapeutic targets in stroke. Key messages PPARα/γ agonist aleglitazar improves stroke outcome after transient brain ischemia.Aleglitazar attenuates inflammatory responses in post-ischemic brain.Aleglitazar reduces microglia migration, phagocytosis, and release of cytokines.Beneficial effects of aleglitazar independent of glucose regulation.Aleglitazar provides extended window of opportunity for stroke treatment.

Parkinson disease (PD) is a neurodegenerative disorder characterized by massive loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia often marks the beginning of the disease. Little is known about the role of the nigro-striatal system in olfaction under physiological conditions and the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system. In the present study, we demonstrate a dopaminergic innervation from neurons in the substantia nigra to the olfactory bulb by axonal tracing studies. Injection of two dopaminergic neurotoxins-1-methyl-4-phenylpyridinium and 6-hydroxydopamine-into the olfactory bulb induced a decrease in the number of dopaminergic neurons in the substantia nigra. In turn, ablation of the nigral projection led to impaired olfactory perception. Hyposmia following dopaminergic deafferentation was reversed by treatment with the D1/D2/D3 dopamine receptor agonist rotigotine. Hence, we demonstrate for the first time the existence of a direct dopaminergic projection into the olfactory bulb and identify its origin in the substantia nigra in rats. These observations may provide a neuroanatomical basis for invasion of environmental toxins into the basal ganglia and for hyposmia as frequent symptom in PD.

Background BACE1 (beta site amyloid precursor protein cleaving enzyme 1) is the rate limiting protease in amyloid β production, hence a promising drug target for the treatment of Alzheimer's disease. Inhibition of BACE1, as the major β-secretase in vivo with multiple substrates, however is likely to have mechanism-based adverse effects. We explored the impact of long-term pharmacological inhibition of BACE1 on dendritic spine dynamics, synaptic functions, and cognitive performance of adult mice. Methods Sandwich enzyme-linked immunosorbent assay was used to assess Aβ40 levels in brain and plasma after oral administration of BACE1 inhibitors SCH1682496 or LY2811376. In vivo two-photon microscopy of the somatosensory cortex was performed to monitor structural dynamics of dendritic spines while synaptic functions and plasticity were measured via electrophysiological recordings of excitatory postsynaptic currents and hippocampal long-term potentiation in brain slices. Finally, behavioral tests were performed to analyze the impact of pharmacological inhibition of BACE1 on cognitive performance. Results Dose-dependent decrease of Aβ40 levels in vivo confirmed suppression of BACE1 activity by both inhibitors. Prolonged treatment caused a reduction in spine formation of layer V pyramidal neurons, which recovered after withdrawal of inhibitors. Congruently, the rate of spontaneous and miniature excitatory postsynaptic currents in pyramidal neurons and hippocampal long-term potentiation were reduced in animals treated with BACE1 inhibitors. These effects were not detected in Bace1 −/− mice treated with SCH1682496, confirming BACE1 as the pharmacological target. Described structural and functional changes were associated with cognitive deficits as revealed in behavioral tests. Conclusions Our findings indicate important functions to BACE1 in structural and functional synaptic plasticity in the mature brain, with implications for cognition.

The polymorphic β-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral β-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop β-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and Aβ40/Aβ42 peptide ratio. To determine the nature of such β-amyloid morphotypes, β-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced β-amyloid deposition with the morphological, conformational, and Aβ40/Aβ42 ratio characteristics of β-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced β-amyloid deposits with the characteristics of β-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced β-amyloid deposits, although less prominent, and the induced deposits were similar to the β-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated Aβ in APP transgenic mice can be maintained by seeded conversion.