Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2008 Jun;67(6):523-31.
doi: 10.1097/NEN.0b013e318177eaf4.

Alzheimer disease pathology as a host response

Rudy J Castellani  1 , Hyoung-Gon Lee, Xiongwei Zhu, George Perry, Mark A Smith
Affiliations
Review

Alzheimer disease pathology as a host response

Rudy J Castellani et al. J Neuropathol Exp Neurol. 2008 Jun.

Abstract

Identification of amyloid-beta and tau as the major protein components of senile plaques and neurofibrillary tangles, respectively, led to an exponential increase in investigations of these proteins and their corresponding metabolic pathways in Alzheimer disease (AD). The presumptions inherent in most studies and in the dogma of the amyloid cascade concept are that these hallmark lesions in AD brains contain molecules that drive the disease process, and that the proteinaceous accumulations are themselves toxic. On the other hand, the lesions of AD are, by definition, end-stage, and their relationship to the clinical disease is inconsistent; this has long been known but, generally, has not been acknowledged until relatively recently. Some recent attempts to address the etiology and pathogenesis of AD discard the pathology and focus on the interplay between invisible toxic intermediates, that is, amyloid-beta oligomers and the synapse. The concept that the hallmark lesions may be nontoxic (something we have long suggested) is slowly gaining acceptance. We favor the interpretation that senile plaques and neurofibrillary tangles represent a host response to an upstream pathophysiologic process, and that the therapeutic targeting of lesions, including toxic intermediates, will succeed only in the event that the host response is directly deleterious. Therefore, renewed efforts aimed at elucidating fundamental age-related processes such as oxidative stress and/or inflammatory mediators are warranted.

PubMed Disclaimer

Figures

Figure 1
Figure 1
The microscopic lesions of AD have shaped our views on the etiology and pathogenesis of the disease. The neurofibrillary tangle (A), composed of hyperphosphorylated tau protein accumulated in paired helical filaments, and senile plaques containing amyloid-β (B) and often extensive neuritic pathology (C), accumulate in large numbers in the diseased brain (D). A,C, immunostained for phosphorylated tau, scale bars= 25 μm; B,D, immunostained for amyloid-β, scale bars= 25 μm and 100 μm, respectively.
Figure 2
Figure 2
Host Response Hypothesis. Age-related etiological factors lead to a multitude of host responses among which are the lesions of AD.
See this image and copyright information in PMC

References

    1. Tomlinson BE. Ageing and the dementias. In: Adams JH, Duchen LW, editors. Greenfield’s Neuropathology. London: Oxford University Press; 1992. pp. 1284–410.
    1. Walsh DM, Selkoe DJ. A beta oligomers -a decade of discovery. J Neuro chem. 2007;101:1172–84. - PubMed
    1. Birmingham K, Frantz S. Set back to Alzheimer vaccine studies. Nat Med. 2002;8:199–200. - PubMed
    1. Golde TE. Disease modifying therapy for AD? J Neurochem. 2006;99:689–707. - PubMed
    1. Castellani RJ, Zhu X, Lee HG, et al. Neuropathology and treatment of Alzheimer disease: did we lose the forest for the trees? Expert Rev Neurother. 2007;7:473–85. - PubMed

Publication types