Team:UCL/Background/Neuropathology

WHAT CAUSES ALZHEIMER'S?

Science behind the disease

There are many vying hypotheses that postulate how Alzheimer’s Disease (AD) may arise. Of these, the most well known is the Amyloid Hypothesis. The Amyloid Hypothesis is centred around the ‘senile plaques’ that form in AD brains, and suggests that their removal could be key in halting the progression of the disease, though other hypotheses contradict this precept. So far, no single cause for the disease has been identified, though most AD research focuses around senile plaques. AD is generally accepted to cause three major histopathological changes in brain tissue.

Histopathology: Senile plaques are extracellular deposits of an abnormal form of the waste protein β-amyloid (Aβ), which tangle with cell matter in the brain. These plaques are larger than cell bodies (15-25 um in diameter) and mature to become even denser. The tangling of the plaques, however, is not proportional to the amount of amyloid proteins in an area, and so the process by which the tangling and the plaques are created are still as yet unknown. Aβ is cleaved from a larger precursor protein - amyloid precursor protein (APP). The Aβ peptide is predominantly cleaved to be 40 amino acids in length, that is, Aβ1-40. However, Aβ1-42 and Aβ1-43 nucleate more rapidly into amyloid fibrils than Aβ1-40 does, and are neurotoxic via unknown mechanisms. Strittmatter and Salvensen theorised that other proteins complexed with Aβ to exacerbate the plaque, mainly ApoE, which is another cerebrospinal fluid protein that has a high affinity for Aβ. The functional forms of ApoE aid protease-mediated degradation.

The second pathological feature is the collection of intraneuronal cytoskeletal filaments called neurofibrillary tangles, due to paired helical filaments. These abnormal tangles are made up of poorly soluble, hyperphosphorylated isoforms of Tau, a microtubule-binding protein that is normally soluble. Functional Tau acts as a part of the cell’s ‘cytoskeleton’, which forms the structural support network of a cell. Its dysfunction disrupts the cytoskeleton, making it harder for the cell to carry out essential survival tasks, and engendering cell death. It is thought that tangle formation is aided and perhaps caused by the senile plaques. Plaques and tangles predominantly appear in brain areas involved in learning, memory and emotional behaviours.

The third sign is cell death. Cell death is most apparent in the neocortex, limbic structures, hippocampus, amygdala, and some of the brainstem nuclei. It is cell death that directly causes the symptoms of Alzheimer’s Disease.