Abstract
The single-mutation of genes associated with Alzheimer’s disease (AD) increases the production of Aβ peptides. An elevated concentration of Aβ peptides is prone to aggregation into oligomers and further deposition as plaque. Aβ plaques and neurofibrillary tangles are two hallmarks of AD. In this review, we provide a broad overview of the diverses sources that could lead to AD, which include genetic origins, Aβ peptides and tau protein. We shall discuss on tau protein and tau accumulation, which result in neurofibrillary tangles. We detail the mechanisms of Aβ aggregation, fibril formation and its polymorphism. We then show the possible links between Aβ and tau pathology. Furthermore, we summarize the structural data of Aβ and its precursor protein obtained via Nuclear Magnetic Resonance (NMR) or X-ray crystallography. At the end, we go through the C-terminal and N-terminal truncated Aβ variants. We wish to draw reader’s attention to two predominant and toxic Aβ species, namely Aβ4−42/ and pyroglutamate amyloid-beta peptides, which have been neglected for more than a decade and may be crucial in Aβ pathogenesis due to their dominant presence in the AD brain.
Highlights
Alzheimer’s disease was first recognized by Alois Alzheimer as presenile dementia in 1906
Familial Alzheimer’s Disease (AD) involves a number of single-gene mutations on chromosomes 1, 14 and 21, which corresponds to the abnormal presenilin 2, presenilin 1 and amyloid precursor protein production respectively [13,14,15,16,17], and each of these mutations is believed to play a very important role in the cleavage of APP and affect amyloid β (Aβ) production
The late-onset AD accounts for the major cases of AD, notwithstanding a lack of full understanding, the genetic risk factors, such as the definitively identified apolipoprotein E (APOE) gene on chromosome 19 [18] and the methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) gene on chromosome 6 [19] as well as some other loci [20,21,22,23], are likely to affect the predisposition of AD
Summary
Alzheimer’s disease was first recognized by Alois Alzheimer as presenile dementia in 1906 It is mainly diagnosed in people whose ages are over 65 with the prevalence of Alzheimer’s Disease (AD). One is the gene-related heritable AD, known as the early onset familial Alzheimer’s disease (fAD). The clinical symptoms can appear in a very young age and it accounts for 25% of all AD cases [4] Another type is the sporadic Alzheimer’s disease (sAD), which constitutes the vast majority of AD cases and is apparently influenced by genetic contributions besides non-genetic environmental factors [5,6,7]. One involves the intracellular accumulation of tau protein while the other is on extracellular amyloid aggregation.
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