Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Abstract

The amyloid-␤ (A␤) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of A␤ peptide constitutes a critical event in the early disease pathogenesis. The direct binding between A␤ and apolipoprotein E (apoE) is an important factor implicated in both A␤ clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/A␤ interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed A␤12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length A␤. A␤12-28P binds with high affinity to apoE, preventing its binding to A␤, but has no direct effect on A␤ aggregation. A␤12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of A␤ plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of A␤ in two AD transgenic mice models. The treatment did not affect the levels of soluble A␤ fraction or A␤ oligomers, indicating that inhibition of the apoE/A␤ interaction in vivo has a net effect of increasing A␤ clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with A␤12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.Alzheimer's pathology ͉ memory loss prevention ͉ peptide ͉ transgenic mice ͉ treatment A lzheimer's disease (AD) is the most common neurodegenerative disease worldwide, characterized by a progressive dysfunction in multiple cognitive domains and complex neuropathological features that include accumulation of amyloid-␤ (A␤) followed by synaptic dysfunction, formation of neurofibrillary tangles, and neuronal loss. With the expected increase in AD prevalence, as a function of the population aging, effective treatment for AD is critically needed. Multiple lines of evidence indicate that a disturbance of A␤ homeostasis is a paramount event in early disease pathogenesis (1). A␤ is a hydrophobic 39-to 43-aa peptide, which is derived from cleavage of a larger, synaptic transmembrane protein, the amyloid precursor protein (APP) (2). The accumulation of A␤ in the brain is determined by the rate of its generation versus in situ proteolytic degradation and clearance across the blood-brain-barrier [BBB; for review see Tanzi et al. (3)]. In the setting of increased concentration, A␤ monomers assemble into oligomers and fibrils and eventually become deposited, forming parenchymal plaques and cerebral amyloid angiopathy (CAA).Inheritance of the apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor identified so far. ApoE isotype inheritance modulates the prevalence, age of onset, and the burden of pathology in sporadic AD (4, 5). ApoE binds A␤ with high affinity a...

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Targeting the liver X receptor (LXR) pathway (Koldamova et al 2005b), apoE lipidation state via ABCA1, as well as LDLR, LRP1, and other apoE receptors are potential ways to stimulate apoE-dependent Ab clearance. In terms of apoE-dependent Ab aggregation, interrupting the apoE-Ab interaction may also have therapeutic potential (Sadowski et al 2006). In addition to effects on the apoE/Ab pathway, apoE receptors such as Apoer2 and Vldlr play important roles in synaptic plasticity, tau phosphorylation, and neuroprotection.…”

Immunotherapy Reduces Vascular Amyloid- in PDAPP Mice

“…Currently A␤-targeted therapeutic approaches for AD have not been shown to reduce vascular amyloid deposition in chronic in vivo preclinical paradigms. However, there is evidence that the direct application of amyloid antibodies to the brain (Prada et al, 2007) and blocking the apolipoprotein E/A␤ interaction (Sadowski et al, 2006) reduce VA␤.…”

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin

“…The pathogenesis of neurodegeneration in AD involves the impact of polymorphic proteins, such as amyloid precursor protein (APP), apolipoprotein E (11,12), sortilin-related receptor, low-density lipoprotein receptor class A repeat-containing protein (SORL1) (13), reelin (14), interleukin 1, ␣1-antichymotrypsin, and ␣2-macroglobulin (15,16) on cellular processes, such as APP processing (13), oxidative stress (17,18), and neuronal apoptosis (19)(20)(21). However, A␤ accumulation is considered the major mechanism susceptible to therapy (22).…”