Aproximación neuropatológica a la fisiopatología de la enfermedad de Alzheimer

Abstract

Introduction: Amyloid plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks of Alzheimer disease (AD), but other important lesions are cerebral amyloid angiopathy, glial responses (reactive astrocytes and activated microglia), and a progressive loss of synapses and neurons. The most widely accepted hypothesis on the pathophysiology of AD, termed ¿amyloid cascade hypothesis¿, postulates that amyloid deposition triggers a cascade of adverse events that include, among others, glial responses, tau hyperphosphorylation and aggregation in NFTs, and massive synaptic and neuron losses, that ultimately lead to dementia.

Rationale/hypothesis/aims: We hypothesized that as the disease advances the amyloid cascade becomes progressively independent of its initiator, the Aß peptide, so that removing the plaques from the brain in the symptomatic phase would be insufficient to arrest or rescue Aß downstream effects. We aimed at 1) understanding the progression of the different pathological lesions over the course of the disease and their relationships; and 2) testing whether the clearance of amyloid plaques from the human AD brain by anti-Aß immunization can arrest this pathogenic cascade.

Subjects/methods: We performed postmortem studies using immunohistochemistry and stereology-based quantitative methods on paraffin sections of the hippocampus and temporal associative neocortex of AD patients (including 5 participants in the Phase 2a trial of anti-Aß active immunization AN1792, by Elan Pharmaceuticals Inc.).

Results: Amyloid deposition in the temporal cortex plateaus early after symptom onset, whereas glial responses increase linearly over the clinical course of the disease and parallel the accumulation of NFTs and the progression of cortical atrophy. The increased glial responses occurs mainly in the proximity of dense-core plaques but also in the proximity of NFTs, suggesting a progressive independence from the plaques. Plaque clearance by anti-Aß active immunization in patients with mild-to-moderate AD is associated with subtle improvements in neurite trajectories and tau hyperphosphorylation, but does not rescue tau misfolding/aggregation in NFTs.

Discussion/conclusions: these results support the existence of an amyloid-dependent and an amyloid-independent stages of AD pathophysiology. Amyloid burden remains essentially constant throughout the clinical course of the disease, consistent with the vast majority of amyloid deposition preceding clinical onset (amyloid-dependent stage). By contrast, glial responses increase in parallel to the clinical course, the accumulation of NFTs, and the cortical atrophy, suggesting that they become progressively independent from plaques. Moreover, NFTs persist after plaque clearance upon anti-Aß immunization, confirming that neurodegenerative phenomena become independent of Aß (amyloid-independent stage).