If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?

被引：89

作者：

Haass, Christian ^{[1
,2
,3
]}

Selkoe, Dennis ^{[4
]}

机构：

[1] German Ctr Neurodegenerat Dis DZNE, Munich, Germany

[2] Ludwig Maximilians Univ Munchen, Fac Med, Biomed Ctr BMC, Metab Biochem, Munich, Germany

[3] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[4] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Dept Neurol, Boston, MA 02115 USA

来源：

PLOS BIOLOGY | 2022年 / 20卷 / 07期

关键词：

BETA-PROTEIN; APOLIPOPROTEIN-E; PRECURSOR PROTEIN; MOUSE MODEL; IN-VIVO; MICROGLIA; MUTATION; PATHOLOGY; PRESENILIN-1; GENE;

D O I：

10.1371/journal.pbio.3001694

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Strong genetic evidence supports an imbalance between production and clearance of amyloid beta-protein (A beta) in people with Alzheimer disease (AD). Microglia that are potentially involved in alternative mechanisms are actually integral to the amyloid cascade. Fluid biomarkers and brain imaging place accumulation of A beta at the beginning of molecular and clinical changes in the disease. So why have clinical trials of anti-amyloid therapies not provided clear-cut benefits to patients with AD? Can anti-amyloid therapies robustly decrease A beta in the human brain, and if so, could this lowering be too little, too late? These central questions in research on AD are being urgently addressed.

引用

页数：15

共 82 条

[1]

Alzheimer A, 1995, Clin Anat, V8, P429

[2]

[Anonymous], 2022, SAF EFF STUD GANT PA

[3] Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases (vol 91, pg 56, 2016) [J].

Bacioglu, Mehtap ;

Maia, Luis F. ;

Preische, Oliver ;

Schelle, Juliane ;

Apel, Anja ;

Kaeser, Stephan A. ;

Schweighauser, Manuel ;

Eninger, Timo ;

Lambert, Marius ;

Pilotto, Andrea ;

Shimshek, Derya R. ;

Neumann, Ulf ;

Kahle, Philipp J. ;

Staufenbiel, Matthias ;

Neumann, Manuela ;

Maetzler, Walter ;

Kuhle, Jens ;

Jucker, Mathias .

NEURON, 2016, 91 (02) :494-496

[4] Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease [J].

Bard, F ;

Cannon, C ;

Barbour, R ;

Burke, RL ;

Games, D ;

Grajeda, H ;

Guido, T ;

Hu, K ;

Huang, JP ;

Johnson-Wood, K ;

Khan, K ;

Kholodenko, D ;

Lee, M ;

Lieberburg, I ;

Motter, R ;

Nguyen, M ;

Soriano, F ;

Vasquez, N ;

Weiss, K ;

Welch, B ;

Seubert, P ;

Schenk, D ;

Yednock, T .

NATURE MEDICINE, 2000, 6 (08) :916-919

[5] Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease [J].

Bateman, Randall J. ;

Xiong, Chengjie ;

Benzinger, Tammie L. S. ;

Fagan, Anne M. ;

Goate, Alison ;

Fox, Nick C. ;

Marcus, Daniel S. ;

Cairns, Nigel J. ;

Xie, Xianyun ;

Blazey, Tyler M. ;

Holtzman, David M. ;

Santacruz, Anna ;

Buckles, Virginia ;

Oliver, Angela ;

Moulder, Krista ;

Aisen, Paul S. ;

Ghetti, Bernardino ;

Klunk, William E. ;

McDade, Eric ;

Martins, Ralph N. ;

Masters, Colin L. ;

Mayeux, Richard ;

Ringman, John M. ;

Rossor, Martin N. ;

Schofield, Peter R. ;

Sperling, Reisa A. ;

Salloway, Stephen ;

Morris, John C. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (09) :795-804

[6] RELEASE OF EXCESS AMYLOID BETA-PROTEIN FROM A MUTANT AMYLOID BETA-PROTEIN PRECURSOR [J].

CAI, XD ;

GOLDE, TE ;

YOUNKIN, SG .

SCIENCE, 1993, 259 (5094) :514-516

[7] Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance [J].

Castellano, Joseph M. ;

Kim, Jungsu ;

Stewart, Floy R. ;

Jiang, Hong ;

DeMattos, Ronald B. ;

Patterson, Bruce W. ;

Fagan, Anne M. ;

Morris, John C. ;

Mawuenyega, Kwasi G. ;

Cruchaga, Carlos ;

Goate, Alison M. ;

Bales, Kelly R. ;

Paul, Steven M. ;

Bateman, Randall J. ;

Holtzman, David M. .

SCIENCE TRANSLATIONAL MEDICINE, 2011, 3 (89)

[8] EARLY-ONSET ALZHEIMERS-DISEASE CAUSED BY MUTATIONS AT CODON-717 OF THE BETA-AMYLOID PRECURSOR PROTEIN GENE [J].

CHARTIERHARLIN, MC ;

CRAWFORD, F ;

HOULDEN, H ;

WARREN, A ;

HUGHES, D ;

FIDANI, L ;

GOATE, A ;

ROSSOR, M ;

ROQUES, P ;

HARDY, J ;

MULLAN, M .

NATURE, 1991, 353 (6347) :844-846

[9] The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease [J].

Cheng-Hathaway, Paul J. ;

Reed-Geaghan, Erin G. ;

Jay, Taylor R. ;

Casali, Brad T. ;

Bemiller, Shane M. ;

Puntambekar, Shweta S. ;

von Saucken, Victoria E. ;

Williams, Roxanne Y. ;

Karlo, J. Colleen ;

Moutinho, Miguel ;

Xu, Guixiang ;

Ransohoff, Richard M. ;

Lamb, Bruce T. ;

Landreth, Gary E. .

MOLECULAR NEURODEGENERATION, 2018, 13

[10] Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals [J].

Chhatwal, Jasmeer P. ;

Schultz, Aaron P. ;

Dang, Yifan ;

Ostaszewski, Beth ;

Liu, Lei ;

Yang, Hyun-Sik ;

Johnson, Keith A. ;

Sperling, Reisa A. ;

Selkoe, Dennis J. .

NATURE COMMUNICATIONS, 2020, 11 (01)

← 1 2 3 4 5 6 7 8 9 →