Making Plaques

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Science  13 Feb 2004:
Vol. 303, Issue 5660, pp. 929
DOI: 10.1126/science.303.5660.929a

A hallmark of Alzheimer's disease (AD) is the progressive formation of brain plaques: deposits of insoluble fibrils of β-amyloid protein that are associated with cognitive impairment and neuronal loss. Two apolipoproteins, apoE and clusterin, bind to β-amyloid and promote its aggregation and fibril formation. The absence of either apolipoprotein results in fewer plaques in a transgenic mouse model of AD. Surprisingly, De Mattos et al. observed earlier and increased fibrillar β-amyloid deposits in the brain when the AD mice lacked both apoliproteins. Before this deposition, more soluble β-amyloid was detected, and clearance of soluble β-amyloid was reduced in living mice.

ApoE itself is cleared from the brain by binding to low-density lipoprotein receptor-related protein (LRP), indirectly implicating this neuronal receptor in β-amyloid clearance. But LRP also facilitates processing of the amyloid precursor protein to β-amyloid, thus enhancing its extracellular release. In AD mice expressing high levels of LRP in neurons, Zerbinatti et al. observed an increase in soluble β-amyloid in the brain and observed a parallel increase in cognitive deficits in these mice, supporting a role for the soluble form of β-amyloid in AD pathogenesis. — LDC

Neuron 41, 193 (2004); Proc. Natl. Acad. Sci. U.S.A. 101, 1075 (2004).

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