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. 2005 Nov;167(5):1183-8.
doi: 10.1016/s0002-9440(10)61206-0.

Rous-Whipple Award Lecture. The Alzheimer's brain: finding out what's broken tells us how to fix it

John Q Trojanowski  1 , Virginia M-Y Lee
Affiliations

Rous-Whipple Award Lecture. The Alzheimer's brain: finding out what's broken tells us how to fix it

John Q Trojanowski et al. Am J Pathol. 2005 Nov.
No abstract available

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Figures

Figure 1
Figure 1
The misfolding, fibrillization, and sequestration of tau into filamentous inclusions is schematically depicted and is described in greater detail in the text. Proceeding from the normal neuron on the left, this tau hypothesis of AD neurodegeneration predicts that the cascade of events depicted schematically will compromise the function and viability of neurons (shown to the right) through the pathological conversion of normal tau into PHFtau, which forms NFTs and dystrophic tau neurites thereby depleting levels of functional MT-binding/stabilizing tau below a critical point that results in the depolymerization of MTs and a disruption of axonal transport. As shown on the far right, the dissolution of degenerating tangle and dystrophic neurite-bearing neurons in the AD brain releases abnormal tau into the extracellular space resulting in elevated levels of cerebrospinal fluid (CSF) tau, which is one of the most robust biomarkers of AD in living patients.
Figure 2
Figure 2
The molecular machinery underlying mechanisms of anterograde (directed toward the + end of MTs) and retrograde (directed toward the − end of MTs) axonal transport in neurons by kinesin and dynein motor proteins, respectively, is schematically illustrated. Kinesins and dyneins and other motor-associated proteins move on MTs to transport Golgi-derived vesicles, cytosolic protein complexes, cytoskeletal polymers, and so forth (for further details and additional citations, see Roy et al15).
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References

    1. Forman MS, Trojanowski JQ, Lee VM-Y. Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med. 2004;10:1055–1063. - PubMed
    1. Skovronsky DM, Lee VM-Y, Trojanowski JQ: Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol (in press) - PubMed
    1. Suh Y-H, Checler F. Amyloid precursor protein, presenilins and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev. 2002;54:469–525. - PubMed
    1. Lee VM-Y, Balin BJ, Otvos L, Trojanowski JQ. A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science. 1991;251:675–678. - PubMed
    1. Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VM-Y. Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron. 1993;10:1089–1099. - PubMed

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