The major features of the βAPP and its corresponding gene are summarized in Table 1. βAPP is a single pass intracellular transmembrane protein found in endosomes, lysosomes, the ER, and the Golgi apparatus. It is subject to three distinct proteolytic fates, depending on the relative activity of three different proteases: α-secretase and β-secretase, which are cell surface pro teases, and γ-secretase, which is an atypical protease that cleaves membrane proteins within their trans membrane domains. The predominant fate of ~90% of βAPP is cleavage by the α-secretase (Fig. 1), an event that precludes the formation of the Aβ pep tide because α-secretase cleaves within the Aβ peptide domain. The other ~10% of βAPP is cleaved by the β- and γ-secretases to form either the nontoxic Aβ40 peptide or the Aβ42 peptide. The Aβ42 peptide is thought to be neurotoxic because it is more prone to aggregation than its Aβ40 counterpart, a feature that makes AD a conformational disease like α1AT deficiency (described previously in this chapter). Normally, little Aβ42 peptide is produced, and the factors that determine whether γ-secretase cleavage will produce the Aβ40 or Aβ42 pep tide are not well defined.

Table1. Genes and Proteins Associated With Inherited Susceptibility to Alzheimer Disease

Fig1. The normal processing of β-amyloid precursor protein (βAPP) and the effect on processing of missense variants in the βAPP gene associated with familial Alzheimer disease. The ovals show the locations of the missense changes. (Reproduced with permission from Nussbaum Rl, Ellis CE: Alzheimer’s disease and Parkinson’s disease, N Engl J Med 348:1356–1364, 2003.)

In monogenic AD due to missense substitutions in the gene encoding βAPP (APP), however, several variants lead to the relative overproduction of the Aβ42 peptide. This increase leads to accumulation of the neurotoxic Aβ42, an occurrence that appears to be the central pathogenic event of all forms of AD, monogenic or sporadic. Consistent with this model is the fact that patients with Down syndrome, who possess three copies of the APP gene (which is on chromosome 21), typically develop the neuropathologic changes of AD by 40 years of age. Moreover, pathogenic variants in the AD genes presenilin 1 and presenilin 2 (see Table 1) also lead to increased production of Aβ42. Notably, the amount of the neurotoxic Aβ42 peptide is increased in the serum of individuals with pathogenic variants in the βAPP, presenilin 1, and presenilin 2 genes; furthermore, in cultured cell systems, the expression of mutant βAPP, presenilin 1, and presenilin 2 increases the relative production of Aβ42 peptide by two- to tenfold.

The central role of the Aβ42 peptide in AD is highlighted by the discovery of a coding variant (p.Ala673Thr) in the APP gene (Fig. 2) that protects against both AD and cognitive decline in older adults. The protective effect is likely due to reduced formation of the Aβ42 peptide, reflecting the proximity of Thr673 to the β-secretase cleavage site (see Fig. 2).

Fig2. The topology of the amyloid precursor protein (βAPP), its nonamyloidogenic cleavage by α-secretase, and its alternative cleavage by putative β-secretase and γ-secretase to generate the amyloidogenic β amyloid peptide (Aβ). letters are the single-letter code for amino acids in β-amyloid precursor protein, and numbers show the position of the affected amino acid. Normal residues involved in missense variants are shown in highlighted circles, whereas the amino acid residues representing various missense pathogenic variants are shown in boxes. The mutated amino acid residues are near the sites of β-, α-, and γ-secretase cleavage (black arrowheads). The pathogenic variants lead to the accumulation of toxic peptide Aβ42 rather than the wild-type Aβ40 peptide. The location of the protective allele Ala673Thr is indicated by the dashed arrow. (Reproduced with permission from Nussbaum Rl, Ellis CE: Alzheimer’s disease and Parkinson’s disease, N Engl J Med 348:1356–1364, 2003.)

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تطلق مسابقتها الثقافية بذكرى ولادة الإمام زين العابدين (عليه السلام)

العتبة العباسية المقدسة تكرّم 1000 طالبة من المرتديات العباءة العراقية في مدارس الديوانية

العتبة العباسية المقدسة تؤكد أهمية الحجاب كجزء من منظومة الواجبات الشرعية

العتبة العباسية المقدسة تقيم مهرجانها السنوي الأوَّل لتكريم الطالبات المرتديات للعباءة العراقية في المدارس

المزيد

الآخبار الصحية

الخبز الأسمر أم الأبيض.. أيهما أفضل لضبط سكر الدم؟

عقاقير التخسيس و"الانتحار".. الحكومة الأميركية تحسم الجدل

الهرم الغذائي الجديد.. لماذا يعد "انقلابا" في خارطة الطعام؟

لحماية ظهرك وقلبك في آن واحد.. ما وضعية النوم الصحيحة؟

المزيد

الآخبار التكنلوجية

كيف يعزز الضوء الطبيعي تفكيرك وانتباهك خلال اليوم

سابقة.. طاقم من محطة الفضاء الدولية يعود إلى الأرض مبكرا

منصات التواصل تضرّ بنفسية المراهقين… والفتيات الأكثر تأثرا

ابتكار ألماني قد يغيّر مستقبل صناعة البلاستيك

المزيد

مواضيع ذات صلة

Nonstandard Base Pairing Often Occurs Between Codons and Anticodons

The Folded Structure of tRNA Promotes Its Decoding Functions

Messenger RNA Carries Information from DNA in a Three-Letter Genetic Code

Transcription of Protein-Coding Genes and Formation of Functional mRNA

DNA Can Undergo Reversible Strand Separation

Native DNA Is a Double Helix of Complementary Antiparallel Strands

A Nucleic Acid Strand Is a Linear Polymer with End-to-End Directionality

Abnormalities of Chromosome Structure

Impact of Genomic Variation

Variation in individual Genomes

Variation in gene Expression and its relevance to medicine

Allelic Imbalance in gene expression