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Targets and Strategies Toward the Development of Alzheimer Therapeutics

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Part of the Topics in Medicinal Chemistry book series (TMC,volume 24)

Abstract

Although Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting tens of millions worldwide, there are no effective disease-modifying therapies and only a handful of symptomatic treatments. Much has been deciphered regarding the molecular basis of AD in the past 25 years, but serious gaps in understanding remain. Aggregation-prone proteins amyloid-β (Aβ) and tau are apparently central to disease pathogenesis and progression; however, the neurotoxic forms of both proteins and the connection between the two remain unclear. Genetic mutations in the precursor protein for Aβ and in a protease that produces Aβ from this precursor cause dominantly inherited early-onset AD. In contrast, an allelic variant of apolipoprotein E is a major risk factor for the much more common late-onset AD, and the encoded protein is critical for Aβ clearance from the brain. Tau is mutated in other forms of dementia, and tau pathology correlates better with neurodegeneration and progression than does Aβ pathology. A variety of therapeutic agents are advancing through the pipeline, many targeting Aβ and tau. New symptomatic treatments are still needed for those who have already progressed too far in the disease process. Advances in drug discovery, new diagnostic tools such as Aβ imaging agents, and improvements in clinical trial design increase the likelihood that effective agents that slow or halt the progression of AD will soon be realized.

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Abbreviations

5-HT:

5-Hydroxytryptamine or serotonin

AD:

Alzheimer’s disease

ApoE:

Apolipoprotein E

APP:

Amyloid-β protein precursor

Aβ:

Amyloid-β protein

BACE:

β-Site APP-cleaving enzyme

CDK:

Cyclin-dependent kinase

CSF:

Cerebrospinal fluid

CTF-β or –β:

C-Terminal fragment generated by β- or β-secretases

FAD:

Familial Alzheimer’s disease

FDA:

Food and Drug Administration

GSK:

Glycogen synthase kinase

MARK:

Microtubule affinity-regulating kinase

MCI:

Mild cognitive impairment

NMDA:

N-Methyl-d-aspartate

PET:

Positron emission tomography

PS1 or PS2:

Presenilin-1 or presenilin-2

SAD:

Sporadic Alzheimer’s disease

USP:

Ubiquitin-specific protease

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Acknowledgments

I thank all the contributing authors to this special issue on important approaches to the diagnosis and treatment of AD.

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Correspondence to Michael S. Wolfe .

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Wolfe, M.S. (2016). Targets and Strategies Toward the Development of Alzheimer Therapeutics. In: Wolfe, M. (eds) Alzheimer’s Disease II. Topics in Medicinal Chemistry, vol 24. Springer, Cham. https://doi.org/10.1007/7355_2016_14

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