P4‐445: Early and chronic treatment with dantrolene blocked later learning and memory deficits in older Alzheimer's triple transgenic mice

Abstract

Background: The major neuropathological hallmarks in the brains of AD patients are senile plaques formed by beta amyloid (As) aggregates and neurofibrillary tangles, containing hyperphosphorylated tau, both causing progressive neuronal dysfunction. These pathological alterations are likely causally involved in eventual neuronal death, particularly in brain regions related to memory and cognition. The first attempt to develop an active vaccine to As, AN1793, failed in clinical trials due to a Th1 type T cell immune response, attributed to the adjuvant used, QS21 and polysorbate 80, provoking a meningoencephalitis-like effect and death in 6% of the patients. To overcome this failure, we designed a novel As1-42 active vaccine incorporated and delivered in a liposomal adjuvant that evoked aTh2 T cell reaction. Methods: As was incorporated and delivered in a liposomal matrix composed of phosphatidylcholine: phosphatidylglycerol: cholesterol:sphingosine-1-phosphate (EB101) and administered intraperitoneally for seven months to double transgenic mice (B6C3-Tg (APPswe,PSEN1dE9)), before or after the AD pathology was developed (In 7-week and 37-week old mice respectively). As plaques and neurofibrillary tangles were quantified by ELISAs and brain histology using specific antibodies. Basal immunological interaction between the T-cells in the affected hippocampalarea and other immune activation markers, including glial fibrillary acidicprotein (GFAP) (astroglia) and CD-45 (B-cells) were also studied using immunoreactive-specific staining. T-cell reaction type was assessed by cytokine type production. Results: Both preventive and therapeutic vaccination with EB101 resulted in a marked inhibition of As deposits (60 to 80%), a reduction of neurofibrillary tangles (70 to 90%) and almost completely suppression of reactive gliosis as measured by GFAP immunoreactivity and cytokine profile, consistent with a marked decrease in amyloidosis-induced inflammation. No external neurological deficits were observed as a result of EB101 immunization (limb paralysis or brain atrophy). Psychomotor and cognitive tests performed in a rota-rod in these animals also showed a dramatic improvement in learning and psychomotor activity in the EB101-treated group. Conclusions: The present findings unequivocally indicate that immunization with EB101 not only prevents and reverses AD neuropathology and underlined inflammation, but also improves cognitive symptoms, thus warranting further studies.