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

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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.

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Abbreviations

Aβ:

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

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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.

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Authors and Affiliations

  1. Axe Neurosciences, Centre de Recherche du CHU de Québec, 2705, Boulevard Laurier, Quebec, QC, G1V 4G2, Canada

    Isabelle St-Amour, Francesca Cicchetti & Frédéric Calon

  2. Département de Psychiatrie & Neurosciences, Faculté de médecine, Université Laval, Quebec, QC, Canada

    Isabelle St-Amour & Francesca Cicchetti

  3. Faculté de pharmacie, Université Laval, Quebec, QC, Canada

    Isabelle St-Amour & Frédéric Calon

Authors
  1. Isabelle St-Amour
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  2. Francesca Cicchetti
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  3. Frédéric Calon
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Corresponding author

Correspondence to Frédéric Calon.

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St-Amour, I., Cicchetti, F. & Calon, F. Immunotherapies in Alzheimer’s disease: Too much, too little, too late or off-target?. Acta Neuropathol 131, 481–504 (2016). https://doi.org/10.1007/s00401-015-1518-9

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  • DOI: https://doi.org/10.1007/s00401-015-1518-9

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