Abstract
Alzheimer’s disease (AD) is a complex, multifactorial disease involving many pathological mechanisms. Nonetheless, single pathogenic mutations in amyloid precursor protein (APP) or presenilin 1 or 2 can cause AD with almost all of the clinical and neuropathological features, and therefore, we believe an important mechanism of pathogenesis in AD could be revealed from examining pathogenic APP missense mutations. A comprehensive review of the literature, including clinical, neuropathological, cellular and animal model data, was conducted through PubMed and the databases of Alzforum mutations, HGMD, UniProt, and AD&FTDMDB. Pearson correlation analysis combining the clinical and neuropathological data and aspects of mutant APP processing in cellular models was performed. We find that an increase in Aβ42 has a significant positive correlation with the appearance of neurofibrillary tangles (NFTs) and tends to cause an earlier age of AD onset, while an increase in Aβ40 significantly increases the age at death. The increase in the α-carboxyl terminal fragment (CTF) has a significantly negative correlation with the age of AD onset, and β-CTF has a similar effect without statistical significance. Animal models show that intracellular Aβ is critical for memory defects. Based on these results and the fact that amyloid plaque burden correlates much less well with cognitive impairment than do NFT counts, we propose a “snowball hypothesis”: the accumulation of intraneuronal NFTs caused by extracellular Aβ42 and the increase in intraneuronal APP proteolytic products (CTFs and Aβs) could cause cellular organelle stress that leads to neurodegeneration in AD, which then resembles the formation of abnormal protein “snowballs” both inside and outside of neurons.
Highlights
With an estimated 5.5 million cases to date, Alzheimer’s disease (AD) is one of the most prevalent neurological dementia disorders in the United States, and the number of cases is projected to rise to over 13 million by 2050 [1]
Fewer than 2% of AD cases belong to early-onset familial AD (EOFAD). 10% to 15% of EOFAD are caused by amyloid precursor protein (APP) mutation, and 20% to 70% of EOFAD are caused by presenilin 1 (PS1) mutation; in rare cases, EOFAD can be caused by presenilin 2 (PS2) mutations [4]
We review the clinical and neuropathological characteristics of AD caused by APP missense mutations, mutant APP processing in cellular models, and the histological and behavioral manifestations of transgenic (Tg) animal models
Summary
According to the patterns of total Aβ, Aβ40, Aβ42 secreted from cellular models, Hunter and Brayne divided these mutations into three groups: Group 1 shows increases in total secreted Aβ, Aβ40, Aβ42 and the ratio of Aβ42/Aβ40, and includes KM670/671NL, A673V, D678N, E682K, K687N, and A692G; Group 2 shows reductions in total secreted Aβ, Aβ40, Aβ42 and the ratio of Aβ42/Aβ40, and includes E693del, E693G, E693K, and E693Q; Group 3 shows reductions in total secreted Aβ and Aβ40 combined with increased Aβ42 and the ratio of Aβ42/Aβ40, and include T714I, V715A, V715M, I716F, I716V, V717F, V717G, V717I, V717L, and K724N [8]. Based on our analysis and the fact that amyloid plaque burden correlates much less well with degree of cognitive impairment than NFTs counts do, we propose the Snowball Hypothesis, a theory encompassing observed phenomena, as the ACH attempted to do with the Aβ peptide, and retaining the scope attempted by the AMA This theory posits that the accumulation of extracellular Aβ42 does not directly cause neuronal death or dysfunction — instead, it induces stress in various protein-handling organelles such as the ER, the Golgi/TGN, and endosomes. Extracellular Aβ42 and intracellular APP proteolytic products (CTFs and Aβs) cause organelle stress and abnormal activation of kinases, which induce hyperphosphorylation of tau and subsequently lead to the formation of NFTs. 3. Therapeutic opportunities rely on elimination of abnormal APP metabolism and relief of organelle stress in neurons
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