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Review
. 2003 Jan;111(1):11-8.
doi: 10.1172/JCI17527.

Alzheimer disease therapy: can the amyloid cascade be halted?

Todd E Golde  1
Affiliations
Review

Alzheimer disease therapy: can the amyloid cascade be halted?

Todd E Golde. J Clin Invest. 2003 Jan.
No abstract available

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Figures

Figure 1
Figure 1
Aβ generation, aggregation, and sites for therapeutic intervention. APP is a type I transmembrane protein that is processed in several different pathways. The Aβ generation pathway is shown. Generation of Aβ in the β-secretase pathway requires two proteolytic events, a proteolytic cleavage at the amino-terminus of the Aβ sequence, referred to as β-secretase cleavage, and a cleavage at the carboxy-terminus, known as γ-secretase cleavage, which results in another carboxy-terminal fragment (CTFγ). Although many Aβ peptides of various lengths can be produced in this fashion, the two of most interest are Aβ40, which is the predominant Aβ peptide, and Aβ42, which is typically produced at much lower levels than Aβ40. Although both peptides can aggregate, Aβ42 is thought to aggregate much more rapidly and to seed the aggregation of Aβ40. Sites for anti-Aβ intervention are indicated. Scissors indicate proteolytic cleavages. “sAPPβ” refers to the large secreted derivative generated by β-secretase cleavage of APP.
Figure 2
Figure 2
Aβ aggregation as the cause of AD. A modified version of the amyloid cascade hypothesis is shown. This version takes into account the possibility that Aβ aggregates other than those found in classic amyloid deposits initiate the pathological cascade. It is possible that Aβ-induced toxicity in turn results in alterations in the brain, such as increased APP and apoE expression, that enhance Aβ deposition, although this is not shown in the figure. Besides known genetic pathways, a pathway in which normal Aβ levels in the context of normal aging may lead to Aβ accumulation is shown. “APPSw” refers to the APP Swedish mutant linked to familial AD; this mutation alters the lysine-methionine sequence immediately preceding Aβ to asparagine-leucine. Trisomy 21 is also known as Down syndrome.
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