Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Abstract

Amyloid β-peptide (Aβ) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Aβ immunization or passive administration of Aβ antibodies markedly reduces Aβ levels and reverses behavioral impairment. However, a human trial of Aβ immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Aβ plaques in an AD mouse model. This effect did not require the presence of antibody, as it was observed in B cell-deficient (Ig m-null) mice. Vaccinated animals developed activated microglia that colocalized with Aβ fibrils, and the extent of microglial activation correlated strongly with the decrease in Aβ fibrils. Activation of microglia and clearing of Aβ occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Aβ through the utilization of compounds that have been safely tested on or are currently in use in humans. IntroductionAlzheimer disease (AD) is the most common form of senile dementia, affecting more than 18 million people worldwide. With increased life expectancy, this number is expected to rise in the future. AD is characterized by widespread functional disturbance of the human brain. The classical neuropathological features are senile plaques, neurofibrillary tangles composed of paired helical filaments, and dystrophic neuritis. Compact senile plaques composed of amyloid β-peptide (Aβ) fibrils are associated with pathological changes in the surrounding brain neurons that lead to their death. Aβ appears to play a key pathogenic role in AD (1), and studies have connected the Aβ plaque with formation of intracellular tau tangles, another neurotoxic feature of AD (2, 3).A body of work has accumulated demonstrating that anti-Aβ antibodies are effective in clearance of amyloid deposits in vitro and in amyloid precursor protein-Tg (APP-Tg) mice (4-10). Solomon et al. showed in vitro that anti-Aβ antibodies can lead to disaggregation of Aβ fibrils, restoring Aβ solubility and thus prevent neurotoxic effects on cell lines (11, 12). Schenk et al. then demonstrated that parenteral immunization of APP-Tg mice with synthetic Aβ in complete Freund adjuvant (CFA) markedly decreased the number and density of Aβ deposits in the brain, with concomitant

T cell independent mechanism for copolymer‐1‐induced neuroprotection

“…These results questioned the role of T cells in Cop-1-mediated neuroprotection, and led us to postulate additional mechanisms mediating Cop-1-induced neuroprotection. Based on the observations made in this report and previously published works [11,12,16,18,49], we suggest that in neurodegenerative conditions, Cop-1 can affect neuroprotective outcomes by at least two independent mechanisms: (i) DC, directly delivering Cop-1 to injury sites where Cop-1 is released and directly affecting neurons, and (ii) induction of T cell-mediated response. This dual effect likely produces the rapid and long-lasting effect of Cop-1 during disease [11, 12, 15-17, 23, 50-52].…”

“…Cop-1 elicits neuroprotective responses in animal models of neuroimmune, neurodegenerative, metabolic, and traumatic disorders [14]. This includes, but is not limited to, optic nerve injury [11], head trauma [15], Parkinson's disease [12], Alzheimer's disease [16], HIV-1-encephalitis [13], glaucoma [17], and experimentally induced encephalitis [18].…”

Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

“…Untreated Tg-AD mice showed consistent and long-lasting impairments in spatial memory tasks. In contrast, performance of the MWM test by the GA-vaccinated Tg-AD mice was rather similar, on average, to that of their age-matched naïve non-Tg littermates (triangles; n ϭ 6) [three-way ANOVA, repeated measures: groups, df (2,16), F ϭ 22.3, P Ͻ 0.0002; trials, df (3,48), F ϭ 67.9, P Ͻ 0.0001; days, df (3,48), F ϭ 3.1, P Ͻ 0.035, for the acquisition phase; and groups, df (2,16), F ϭ 14.9, P Ͻ 0.0003; trials, df (3,48), F ϭ 21.7, P Ͻ 0.0001; days, df (1,16), F ϭ 16.9, P Ͻ 0.0008, for the reversal phase].…”

“…AD progression has been attributed, in part, to the microgliamediated local immune response, which apparently does not operate in the optimal way needed to fight off the adverse conditions (3,4). Studies from our laboratory have shown that recovery from CNS injury is critically dependent on the well controlled activity of T cells directed to specific CNS autoantigens (5,6).…”

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

“…A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16)(17)(18)(19)(20)(21)(22)(23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26).…”