TY - JOUR
T1 - Targeting Aβ and tau in Alzheimer's disease, an early interim report
AU - Golde, Todd E.
AU - Petrucelli, Leonard
AU - Lewis, Jada
N1 - Funding Information:
This work was supported by the Mayo Clinic (to TG, LP, and JL); the National Institutes of Health/National Institute on Aging Grants RO1AG18454 (T.G.), RO1AG29886 , P01AG25531 , R01AG026251 (L.P.), and P01-AG17216-08 (L.P.); the National Institutes of Health/National Institute of Neurological Disorders and Stroke Grant RO1NS39072 (T.G.), R21NS055698 (L.P.), and R21NS059363 (L.P.); the National Institute of Neurological Diseases and Stroke R01-NS046355 (J.L.); the Johnnie B. Byrd Sr. Alzheimer's Research Institute and Center 2005A108 (J.L.); and the Alzheimer's Association IIRG-06-27277-1 (to J.L.). T.G. is supported by Rotarians in South Carolina, Georgia , and North Carolina through the CART fund .
PY - 2010/6
Y1 - 2010/6
N2 - The amyloid β (Aβ) and tau proteins, which misfold, aggregate, and accumulate in the Alzheimer's disease (AD) brain, are implicated as central factors in a complex neurodegenerative cascade. Studies of mutations that cause early onset AD and promote Aβ accumulation in the brain strongly support the notion that inhibiting Aβ aggregation will prevent AD. Similarly, genetic studies of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17 MAPT) showing that mutations in the MAPT gene encoding tau lead to abnormal tau accumulation and neurodegeneration. Such genetic studies clearly show that tau dysfunction and aggregation can be central to neurodegeneration, however, most likely in a secondary fashion in relation to AD. Additional pathologic, biochemical, and modeling studies further support the concept that Aβ and tau are prime targets for disease modifying therapies in AD. Treatment strategies aimed at preventing the aggregation and accumulation of Aβ, tau, or both proteins should therefore be theoretically possible, assuming that treatment can be initiated before either irreversible damage is present or downstream, self-sustaining, pathological cascades have been initiated. Herein, we will review recent advances and also potential setbacks with respect to the myriad of therapeutic strategies that are designed to slow down, prevent, or clear the accumulation of either "pathological" Aβ or tau. We will also discuss the need for thoughtful prioritization with respect to clinical development of the preclinically validated modifiers of Aβ and tau pathology. The current number of candidate therapies targeting Aβ is becoming so large that a triage process is clearly needed to insure that resources are invested in a way such that the best candidates for disease modifying therapy are rapidly moved toward clinical trials. Finally, we will discuss the challenges for an appropriate "triage" after potential disease modifying therapies targeting tau and Aβ have entered clinical trials.
AB - The amyloid β (Aβ) and tau proteins, which misfold, aggregate, and accumulate in the Alzheimer's disease (AD) brain, are implicated as central factors in a complex neurodegenerative cascade. Studies of mutations that cause early onset AD and promote Aβ accumulation in the brain strongly support the notion that inhibiting Aβ aggregation will prevent AD. Similarly, genetic studies of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17 MAPT) showing that mutations in the MAPT gene encoding tau lead to abnormal tau accumulation and neurodegeneration. Such genetic studies clearly show that tau dysfunction and aggregation can be central to neurodegeneration, however, most likely in a secondary fashion in relation to AD. Additional pathologic, biochemical, and modeling studies further support the concept that Aβ and tau are prime targets for disease modifying therapies in AD. Treatment strategies aimed at preventing the aggregation and accumulation of Aβ, tau, or both proteins should therefore be theoretically possible, assuming that treatment can be initiated before either irreversible damage is present or downstream, self-sustaining, pathological cascades have been initiated. Herein, we will review recent advances and also potential setbacks with respect to the myriad of therapeutic strategies that are designed to slow down, prevent, or clear the accumulation of either "pathological" Aβ or tau. We will also discuss the need for thoughtful prioritization with respect to clinical development of the preclinically validated modifiers of Aβ and tau pathology. The current number of candidate therapies targeting Aβ is becoming so large that a triage process is clearly needed to insure that resources are invested in a way such that the best candidates for disease modifying therapy are rapidly moved toward clinical trials. Finally, we will discuss the challenges for an appropriate "triage" after potential disease modifying therapies targeting tau and Aβ have entered clinical trials.
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U2 - 10.1016/j.expneurol.2009.07.035
DO - 10.1016/j.expneurol.2009.07.035
M3 - Review article
C2 - 19716367
AN - SCOPUS:77952549757
SN - 0014-4886
VL - 223
SP - 252
EP - 266
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -