Department of Medicine

Neurobiology of Alzheimer's Disease

Dr Magdalena Sastre

Alzheimer’s disease (AD) is the most common form of dementia. Genetic and pathological evidence supports the amyloid cascade hypothesis of AD, which states that amyloid-β (Aβ), a proteolytic derivative of a larger amyloid precursor protein (APP) has a vital role in all cases of AD (Fig.1). The age-dependent accumulation and deposition of Aβ peptides in the brain is causal and triggers downstream pathologies and progressive dementia. The regulation of amyloid synthesis and/or clearance could lead to new therapeutic strategies for AD.

figure 1


Figure 1. Aβ peptide that accumulates in the brain of AD patients is generated by the enzymatic cleavage of a larger Amyloid Precursor Protein (APP)

There is strong evidence that Aβ toxicity could be mediated through the induction of inflammatory events in the brain. During the last few years it has been speculated that the inflammatory response associated with the presence of neuritic plaques could be involved in neuronal damage and contribute to the progression of the disease. Activated microglia and reactive astrocytes surrounding extracellular deposits of Aβ initiate an inflammatory response, characterised by a local cytokine-mediated acute-phase response, activation of the complement cascade and subsequent further cell damage (Fig. 2). Our work supports the hypothesis that inflammation affects AD pathology by increasing the generation of Aβ due to increased steady-state mRNA levels, expression and activity of the ß-secretase or BACE (Sastre et al, 2003), which is the main enzyme responsible for Aβ generation.

Larger figure 2

Figure 2. Microglia and astrocytes surrounding Aβ neuritic plaques initiate an inflammatory response that could have deleterious consequences for neuronal survival.

On the other hand, the use of non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to be protective against the development of AD. We have reported that the molecular mechanism behind this effect could be related to decreases in BACE1 transcription (Sastre et al, 2003, 2006). Ibuprofen and other NSAIDs are able to decrease total Aβ levels only under inflammatory conditions and this effect seems to be mediated by Peroxisome Proliferator-activated receptor-γ (PPARγ). Our data support the use of PPARγ agonists in the treatment of Alzheimer's disease.

The current work in our lab is related to the investigation of other factors and signalling cascades that influence PPARγ  activity and other additional intracellular pathways involved in inflammation. We are also exploring further anti-inflammatory proteins that are released by glial cells and that could restore brain function by reducing the deleterious effects of Aβ and allow identifying new targets for therapeutic intervention.

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Neurobiology of Alzheimer's


  • Alzheimer's Research Trust Major Project Grant 2009
  • Alzheimer's research Trust Pilot Project Grant 2009
  • Alzheimer’s Research UK PhD fellowship 2011
  • Alzheimer’s Research UK Research grant 2011
  • Johnson & Johnson/Imperial Innovations 2012