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Thursday September 21 2017

Pathoprofile: Alzheimer’s

Alzheimer’s disease is an age-related neurodegenerative disorder characterized by gradual cognitive decline. With 44 million people affected worldwide, it is one society’s most prevalent degenerative diseases. The number of Canadians suffering from Alzheimer’s or a related form of dementia is estimated to double to around 1.3 million people within the next generation. This could be due to the repercussions of chronic stress over longer life expectancies.

Neurological Features 

There are two types of Alzheimer’s: early-onset (familial) Alzheimer’s and late-onset (sporadic) Alzheimer’s. Despite its enigmatic etiology, a growing body of research has noted several hallmark symptoms of familial Alzheimer’s including loss of neurons, general atrophy of the brain, such as amyloid-plaques and neurofibrillary tangles (NFTs).5 Two of the most prominent pathological features of the disease, A42 peptide plaques and hyperphosphorylated tau tangles, are integral to understanding the progressive cognitive decline associated with familial Alzheimer’s.

APP Cleavage

The APP gene encodes an amyloid precursor protein (APP), an inactive protein that must undergo modifications before its conversion to an activated form. While the function of APP remains elusive, growing research suggests that it may play a role in neuronal growth and repair. Normally, APP is initially cleaved by the enzymes, -secretase and -secretase, forming an -stub and a -stub, respectively. These cleavage products are further cleaved by -secretase, an enzyme complex comprised of four proteins – Nicastrin, Aph1, Pen-2, and the catalytic core presenilin. Following cleavage, the -stub generates a p3 peptide, and the -stub produces an extracellular C-terminal fragment, an intracellular domain fragment, and a variable amyloid- (A) peptide. This peptide can exist in different forms with lengths ranging from 39 to 49 residues; in particular, the peptide most commonly exists as A40 or A42.7,8 Accumulation of the more toxic A42 isoform instigates the aggregation of amyloid plaques.

Recent studies have demonstrated that certain presenilin (Ps) mutations can alter the site of APP cleavage and subsequently increase the A42/A40 ratio.6 These mutations additionally reduce the catalytic efficiency of -secretase, favouring the production of peptides of longer lengths, such as A42.6 Because of their key role in APP cleavage, -secretase and its catalytic core, presenilin, have become attractive therapeutic targets for Alzheimer’s disease.

Tau Tangles

Growing evidence suggests that APP and Ps mutations are associated not only with amyloid plaques, but also with neurofibrillary tangles (NFTs). NFTs are aggregates of hyperphosphorylated tau proteins that accumulate in brain regions critical to cognitive function. Responsible for stabilizing microtubules, tau supports the neuronal cytoskeleton and facilitates axonal transport. However, following aberrant modifications, tau triggers the synaptic loss and neuronal death characteristic of Alzheimer’s. According to recent research, the A peptides comprising amyloid plaques may also contribute to the formation of NFTs.9,10 In particular, A activates caspases involved in programmed cell death, or apoptosis. Caspase activation induces cleavage of tau at its carboxy-terminus, and the resulting tau fragments assemble more rapidly into filaments. Further conformational changes initiate and accelerate tau phosphorylation and aggregation. Tangled and twisted, the filaments impede axonal transport and impair neuronal function, ultimately leading to the potentiation of caspase-mediated apoptotis. Given the significant role of NFTs in neurodegeneration, studies continue to investigate the therapeutic potential of inhibiting abnormal hyperphosphorylation and disassembling filament aggregates.

By Valerie Kim and Jessica Chee

References may be found in the journal.

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The Meducator is McMaster University’s undergraduate Health Sciences Journal. It publishes pieces that critically address current issues with a high degree of scientific rigor, but in a way that is accessible to a broad audience.

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