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Acta Neuropathologica

, Volume 131, Issue 4, pp 481–504 | Cite as

Immunotherapies in Alzheimer’s disease: Too much, too little, too late or off-target?

  • Isabelle St-Amour
  • Francesca Cicchetti
  • Frédéric CalonEmail author
Review

Abstract

Years of research have highlighted the importance of the immune system in Alzheimer’s disease (AD), a system that, if manipulated during strategic time windows, could potentially be tackled to treat this disorder. However, to minimize adverse effects, it is essential to first grasp which exact aspect of it may be targeted. Several clues have been collected over the years regarding specific immune players strongly modulated during different stages of AD progression. However, the inherent complexity of the immune system as well as conflicting data make it quite challenging to pinpoint a specific immune target in AD. In this review, we discuss immune-related abnormalities observed in the periphery as well as in the brain of AD patients, in relation to known risk factors of AD such as genetics, type-2 diabetes or obesity, aging, physical inactivity and hypertension. Although not investigated yet in clinical trials, C5 complement system component, CD40/CD40L interactions and the CXCR2 pathway are altered in AD patients and may represent potential therapeutic targets. Immunotherapies tested in a clinical context, those aiming to attenuate the innate immune response and those used to facilitate the removal of pathological proteins, are further discussed to try and understand the causes of the limited success reached. The prevailing eagerness to move basic research data to clinic should not overshadow the fact that a careful preclinical characterization of a drug is still required to ultimately improve the chance of clinical success. Finally, specific elements to consider prior to initiate large-scale trials are highlighted and include the replication of preclinical data, the use of small-scale human studies, the sub-typing of AD patients and the determination of pharmacokinetic and pharmacodynamics parameters such as brain bioavailability and target engagement.

Keywords

Blood–brain barrier Immunization Clinical trials Immunoglobulins IVIg Lymphocytes 

Abbreviations

Amyloid-β peptide

AD

Alzheimer’s disease

ALCAM

Activated leukocyte cell adhesion molecule

APOE

Apolipoprotein E

APP

Amyloid precursor protein

BACE

β-Site APP cleaving enzyme

BBB

Blood–brain barrier

CD

Cluster of differentiation

CNS

Central nervous system

COX

Cyclooxygenase

CRP

C reactive protein

CSF

Cerebrospinal fluid

CX3CR1

Chemokine (C-X3-C motif) receptor 1

CXCR2

CXC chemokine receptor 2

EAE

Experimental autoimmune encephalomyelitis

ICAM

Intercellular adhesion molecule

IFN

Interferon

IL

Interleukin

IVIg

Intravenous immunoglobulin

MASPs

Mannose binding lectin-associated serine proteases

MBL

Mannose binding lectin

MCP-1

Monocyte chemoattractant protein-1

MCI

Mild cognitive impairment

MIP

Macrophage inflammatory protein

NFT

Neurofibrillary tangle

NK

Natural killer

NSAID

Nonsteroidal anti-inflammatory drug

PBMC

Peripheral blood mononuclear cells

PECAM

Platelet endothelial cell adhesion molecule

PET

Positron emission tomography

PS

Presenilin

RNA

Ribonucleic acid

s

Soluble

TLR

Toll-like receptor

TNF

Tumor necrosis factor

VCAM

Vascular cell adhesion molecule

Notes

Acknowledgments

IS-A is supported by a CIHR-Huntington Society of Canada postdoctoral fellowship. Fond de Recherche du Québec en Santé provided salary support to FCi and FCa. The authors are grateful to Mr. Alain St-Amour from Si Design & Web for the artwork. FCa has received research grant from Grifols (Mississauga, ON, Canada). The funding source had no involvement in the study design, and in the collection, analysis or interpretation of the data.

Compliance with ethical standards

Conflict of interest

The authors have no other conflict of interest to declare.

Supplementary material

401_2015_1518_MOESM1_ESM.pdf (344 kb)
Supplementary material 1 (PDF 344 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Isabelle St-Amour
    • 1
    • 2
    • 3
  • Francesca Cicchetti
    • 1
    • 2
  • Frédéric Calon
    • 1
    • 3
    Email author
  1. 1.Axe NeurosciencesCentre de Recherche du CHU de QuébecQuebecCanada
  2. 2.Département de Psychiatrie & Neurosciences, Faculté de médecineUniversité LavalQuebecCanada
  3. 3.Faculté de pharmacieUniversité LavalQuebecCanada

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