A Synthetic Peptide Blocking the Apolipoprotein E/β-Amyloid Binding Mitigates β-Amyloid Toxicity and Fibril Formation in Vitro and Reduces β-Amyloid Plaques in Transgenic Mice

Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta; Ripellino, James A.; Li, Yongsheng; Schmidt, Stephen D.; Mathews, Paul M.; Fryer, John Denis; Holtzman, David M.; Sigurdsson, Einar M.; Wısnıewskı, Thomas

doi:10.1016/s0002-9440(10)63355-x

Cited by 137 publications

(179 citation statements)

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“…These modifications decreased the potential immunogenicity and extended the serum half-live (62 Ϯ 7 min; mean Ϯ SEM) but did not affect the ability of A␤12-28P to inhibit apoE/A␤ binding (12, ʈ, **). A␤12-28P is BBB-permeable as has been demonstrated (12). Here, we present results of in vivo studies in two different AD Tg models where A␤12-28P was used to block the apoE/A␤ interaction.…”

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confidence: 76%

“…A␤1-40, A␤12-28, and A␤12-28P peptides were custom-synthesized at the W. M. Keck Facility at Yale University (New Haven, CT) by using solid-phase support, and they were purified as described (11,12,19). A␤12-28P used for in vitro assays was derived from the same batch administered to Tg animals.…”

Section: Methodsmentioning

confidence: 99%

“…A␤12-28P used for in vitro assays was derived from the same batch administered to Tg animals. Lipidated apoE4 complexes were prepared from primary astrocytic cultures derived from apoE4 Tg mice as described (12). Anti-A␤ antibodies were provided by P.D.M.…”

Section: Methodsmentioning

confidence: 99%

“…These observations indicate that the net effect of apoE's involvement in A␤ metabolism favors its deposition over the clearance and also suggests that pharmacological blockade or neutralization of the apoE/A␤ interaction may provide an alternative therapeutic strategy. We and others have demonstrated that short synthetic peptides corresponding to A␤ residues 12-28, which is the apoE binding motif on A␤, can bind to lipidated human apoE and abolish its effect on A␤ aggregation and toxicity in cell culture (12,16). With the aim of testing the effect of blocking the apoE/A␤ interaction on AD pathology in AD Tg models, we have designed a compound based on the A␤12-28 sequence that was modified for in vivo administration.…”

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confidence: 99%

“…ApoE binds A␤ with high affinity and acts as a ''double-edged sword'' in the pathomechanism of AD, being involved in both clearance of A␤ across the BBB (6,7) and the promotion of its deposition (5,8,9). All human apoE isoforms (E2, E3, and E4) promote in vivo assembly of A␤ synthetic peptide into fibrils and enhance A␤ toxicity in tissue culture with E4 producing the most striking effect (10)(11)(12). Knockout of the apoE gene (apoE KO ) in APP V717F AD transgenic (Tg) mice results in a dramatic reduction in A␤ burden associated with a virtual absence of parenchymal fibrillar A␤ deposits and CAA (13)(14)(15).…”

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confidence: 99%

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

Sadowski¹,

Pankiewicz²,

Scholtzova³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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148

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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...

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confidence: 76%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%