Molecular Genetics

Studies focusing on large families with the rare, early-onset, autosomal dominant form of the disease led to the discovery that mutations in the amyloid precursor protein (APP)[9] Presenilin 1 (PSEN1),[10,11] and Presenilin 2 (PSEN2)[12] genes cause AD.

Although these autosomal dominant families represent only a small percentage of the total AD cases, functional studies of the effects of the identified mutations have become an important way to dissect the causes and underlying disease mechanisms leading to AD. Mutations in all three genes produce an increase of plasma amyloid p (Ap42),[13] which forms the core of neuritic plaques found in brains of people with AD.

The APP gene in chromosome 21 (region 21q11.2— q21.1) was the first gene to be associated with early-onset familial AD (AD1).[14] The original clue came from the observation that individuals with Down syndrome, who have chromosome 21 trisomy, invariably develop the clinical and pathological features of AD if they live over 30 years.[15]

The APP gene has 19 exons and encodes the amyloid precursor protein (Ap) of 695-770 amino acids, which is proteolytically cleaved to form Ap, the major component of amyloid plaques in the brain tissue. All APP mutations (16 mutations) occurs in exons 16 and 17.

AD1 accounts for no more than 10-15% of early-onset familial AD.[4] The mean age of AD1 onset is around the early 50s, with a range from 43 to 62 years.[3]

Mutations in PSENl (AD3) located in chromosome 14 (region 14q24.3) are responsible for 30-70% of the AD cases with familial early onset. PSENl gene contains 10 protein-coding exons and is predicted to encode a serpentine protein (467 amino acids) with 7-10 transmembrane domains. To date, at least 130 different mutations have been described in the PSENl gene in more than 200 unrelated families (Fig. 1). Most mutations lie in exon 7 (28 mutations), exon 5 (27 mutations), and exon 8 (23 mutations). The majority of these are missense mutations giving rise to the substitution of a single amino acid (AD mutation database; http://molgen-ww. uia.

It has been speculated that most AD-related mutations result in a gain of function. Mutations in PSENl alter the processing of pAPP by preferentially favoring the production of potentially toxic long-tailed Ap peptides ending at residue 42 or 43.[16]

PSENl mutations are associated with the earliest age of onset (29-62 years) of the three early-onset form genes.[3] It has been described that families of different ethnic backgrounds with the same mutation also exhibit similar ages of onset.

The PSEN2 gene (AD4), a rare cause of early-onset AD (2% of all early-onset familial AD), is located on chromosome 1 (region 1q31-q42) and it was found using sequence homology strategy to the PSEN1. The nine mutations in the PSEN2 gene resulting in AD have been identified in 15 families with a broad range of onset age (40-88 years).[3,12,18,19]

The high similarity in clinical and neuropathological features between the early-onset familial and ''sporadic'' late-onset AD suggests that similar pathophysiological factors are involved.

In the near future, it is probable that other AD genes for early-onset familial AD will be identified because familial pedigrees with several affected members with the early-onset autosomal dominant form and not known mutations in the previously reported genes have been described.[20]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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