Neuropathologic Changes Provide Insights into Key Mechanisms of Alzheimer Disease and Related Dementia

Abstract

Alzheimer disease (AD) is a chronic disease characterized by a progressive decline in memory and cognition. AD progression is closely correlated with neuropathologic changes and accumulation of the two main hallmark lesions, senile plaques and neurofibrillary tangles. Nevertheless, deciphering the complex biological aspects of AD requires looking for the neuropathologic changes not only as the cause but also as the collective response to a disease process that is essential to maintaining life during aging but ultimately generates a nonfunctional brain. Chronic conditions, such as AD, represent a new homeostatic balance or disease state, where the organism responds or adapts to maintain life. The pathologic diagnosis of AD still remains the gold standard for precise diagnosis of dementia, commonly in conjunction with cognitive-memory tests and brain image scans. Herein, we present a general overview of the main neuropathologic hallmarks and features of AD and related dementia, revealing the key biological and functional changes as potential drivers of age-dependent brain failure related to AD. The present work reflects some of the main ideas presented during the American Society for Investigative Pathology Rous-Whipple Award Lecture 2021.

Figure 1

Neuropathologic hallmarks of Alzheimer disease (AD). A: Immunocytochemistry of AD brain tissue section to locate amyloid-β senile plaques. B: Neurofibrillary tangles of phosphorylated tau. Images courtesy of Sandra Siedlak (Case Western Reserve University, Cleveland, OH). Scale bars = 50 μm (A and B).

Figure 2

Oxidative stress in Alzheimer disease (AD). A: Immunolocalization of oxidized proteins (nitrotyrosine) in AD hippocampus [arrows indicate neurons with neurofibrillary tangles (NFTs), arrowheads indicate neurons without NFTs, and asterisks indicate location of senile plaques]. B: Control case (non-AD). C: Lipid peroxidation (4-hydroxy-2-nonenal–pyrrole) immunostaining in AD hippocampus (arrows indicate location of neurons with NFTs, and arrowheads indicate location of neurons without NFTs). Inset: A high-magnification view of a neuron containing an NFT and lipid peroxidation. D: Control (non-AD). E: Immunolocalization of oxidized nucleosides (anti–8-hydroxy-deoxyguanosine and anti–8-hydroxyguanine) in AD hippocampus. F: Control (non-AD). Reproduced with permission from J Neurosci, 1997, 17:2653–2657 (A and B); J Neurochem, 1997, 68:2092–2097 (C and D); and J Neurosci, 1999, 19:1959–1964 (E and F). Scale bars: 100 μm (B); 50 μm (C–F).

Figure 3

Histochemical location of oxidation-reduction–active iron in Alzheimer disease (AD). A: Tissue section from AD brain (arrowheads indicate the presence of neurofibrillary tangles, and arrows indicate amyloid senile plaques). B: Control (non-AD) brain. C: X-ray spectromicroscopy (STXM) image showing the overall plaque morphology. D: Composite STXM image showing plaque morphology (blue), Cu²⁺ (green), Cu⁺/Cu⁰ (red), and iron (gray) content. E: Iron oxidation state difference map of the region highlighted in D. Strongly absorbing oxidized iron (Fe³⁺) is shown as light contrast, and chemically reduced iron (Fe²⁺ and/or Fe⁰) is shown as dark contrast. F: High-resolution (HR) composite image. G: Copper oxidation state difference map of particles G1–G6 of the region highlighted in D. In the oxidation state difference map, oxidized copper (Cu²⁺) is shown as light contrast, and chemically reduced copper (Cu⁺ and/or Cu⁰) is shown as dark contrast. Reproduced with permission from Proc Natl Acad Sci U S A, 1997, 19:9866 (A and B); and Sci Adv, 2021, 7:eabf6707 (C–G). Scale bars: 200 μm (B); 5 μm (C and D); 500 nm (E–G).

Figure 4

Possible mechanisms for oxidative stress in Alzheimer disease. Mitochondria autophagy is responsible for oxidation-reduction (Redox) metal release, leading to cytoplasmic Redox centers (Fenton chemistry) and primary oxidant release (O₂⁻). Aβ, amyloid-β; NFT, neurofibrillary tangle.