Pridopidine Promotes Synaptogenesis and Reduces Spatial Memory Deficits in the Alzheimer's Disease APP/PS1 Mouse Model.

Sigma-1 receptor agonists have recently gained a great deal of interest due to their anti-amnesic, neuroprotective, and neurorestorative properties. Compounds such as PRE-084 or pridopidine (ACR16) are being studied as a potential treatment against cognitive decline associated with neurodegenerative disease, also to include Alzheimer's disease. Here, we performed in vitro experiments using primary neuronal cell cultures from rats to evaluate the abilities of ACR16 and PRE-084 to induce new synapses and spines formation, analyzing the expression of the possible genes and proteins involved. We additionally examined their neuroprotective properties against neuronal death mediated by oxidative stress and excitotoxicity. Both ACR16 and PRE-084 exhibited a concentration-dependent neuroprotective effect against NMDA- and H2O2-related toxicity, in addition to promoting the formation of new synapses and dendritic spines. However, only ACR16 generated dendritic spines involved in new synapse establishment, maintaining a more expanded activation of MAPK/ERK and PI3K/Akt signaling cascades. Consequently, ACR16 was also evaluated in vivo, and a dose of 1.5 mg/kg/day was administered intraperitoneally in APP/PS1 mice before performing the Morris water maze. ACR16 diminished the spatial learning and memory deficits observed in APP/PS1 transgenic mice via PI3K/Akt pathway activation. These data point to ACR16 as a pharmacological tool to prevent synapse loss and memory deficits associated with Alzheimer's disease, due to its neuroprotective properties against oxidative stress and excitotoxicity, as well as the promotion of new synapses and spines through a mechanism that involves AKT and ERK signaling pathways.

Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer's disease.

Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Aß) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer's disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: ß-amyloid (Aß) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Aß in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Aß42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Aß transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Aß burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Aß) and diminished secretion of TTR (less neuroprotection against cortical Aß toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.