Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

Abstract

Alzheimer's disease (AD) is characterized by extensive neurodegeneration and inflammation in selective brain areas, linked to severely disabling cognitive deficits. Before full manifestation, different stages appear with progressively increased brain pathology and cognitive impairment. This significantly extends the time lag between initial molecular triggers and appearance of detectable symptoms. Notably, a number of studies in the last decade have revealed that in the early stage of mild cognitive impairment, events that appear in contrast with neuronal distress may occur. These have been reproduced in vitro and in animal models and include increase in synaptic elements, increase in synaptic and metabolic activity, enhancement of neurotrophic milieu and changes in glial cell reactivity and inflammation. They have been interpreted as compensatory responses that could either delay disease progression or, in the long run, result detrimental. For this reason, these mechanisms define a new and previously undervalued window of opportunity for intervention. Their importance resides especially in their early appearance. Directing efforts to better characterize this stage, in order to identify new pharmacological targets, is an exciting new avenue to future advances in AD research.

Keywords: beta-amyloid; cognitive impairment; compensation; glial reactivity; neurodegeneration.

Figure 1

Compensation as a neuroprotective strategy in AD. A, As Aβ/tau brain pathology increases, compensatory events come into play to counteract the decline in neuronal functions and confer increased tolerance to brain pathology. Inability to adopt compensatory responses results in an earlier decline. B, Compensatory events evenly balance pathological ones in early prodromal stages of disease, but they begin to fail due to overload of pathology in MCI until they are no longer able to efficiently contrast pathology, or even become detrimental, in severe AD