Abstract
Alzheimer's disease (AD) is pathologically defined by the presence of extracellular amyloid plaques comprised of amyloid-β (Aβ) peptides, formation of neurofibrillary tangles, and low-level, chronic neuroinflammation. These pathological hallmarks are posited to work in a concerted manner according to the "amyloid cascade hypothesis," which purports that Aβ deposition as "senile" amyloid plaques is the principal etiopathological event in AD. Despite local recruitment of brain microglia to sites of Aβ deposition, the brain's innate immune system ultimately fails at restricting Aβ plaque formation. It is becoming increasingly clear that inhibitory mechanisms exist to restrict amyloid clearance by both brain-resident and peripheral monocytes, and that innate immune genes can be targeted to reduce AD-like pathology in rodent models of cerebral amyloidosis. This chapter explores the preclinical science behind the expanding field of Aβ immunotherapy and the potential for a new generation of pharmacotherapeutics that promote a beneficial innate immune response in the AD brain.
Original language | English (US) |
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Title of host publication | Genes, Environment and Alzheimer's Disease |
Publisher | Elsevier Inc |
Pages | 361-386 |
Number of pages | 26 |
ISBN (Print) | 9780128028513 |
DOIs | |
State | Published - 2016 |
Funding
We thank Dr Marie-Victoire Guillot-Sestier for helpful discussion and Dr Kevin Doty (USC Zilkha Neurgenetic Institute, Los Angeles, CA, USA) for assistance with the design and creation of Figure 12.1 . D.G. is supported by an NIH National Research Service Award 1F31NS083339-01A1. This work was supported by the National Institute on Aging (5R00AG029726-04 and 3R00AG029726-04S1, to T.T.), the National Institute on Neurologic Disorders and Stroke (1R01NS076794-01, to T.T.), and startup funds from the Zilkha Neurogenetic Institute.
Keywords
- Alzheimer's disease
- Amyloid
- Immunotherapy
- Innate immunity
- Macrophage
- Microglia
- Phagocytosis
ASJC Scopus subject areas
- General Medicine
- General Neuroscience