Amyloid precursor protein, abnormal

Borroni B, Colciaghi F, Caltagirone C, et al. Platelet amyloid precursor protein abnormalities in mild cognitive impairment predict conversion to dementia of Alzheimer type A 2-year follow-up study. Arch Neurol 2003 60(12) 1740-1744. 

Amyloid precursor protein (APP) is the precursor of (3-amyloid, the main component of senile plaques found in the brain of Alzheimer patients. The production of (3-amyloid from APP to the cells from abnormal proteolytic cleavage of the amyloid precursor protein. Enzymes involved in this cleavage may be suitable targets for the therapy of Alzheimer s disease. 

Figure 18.2 Production of senile plaque (S/A4 amyloid protein. Amyloid fS4 protein (/S/A4) is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP. This is a transmembrane protein which is normally cleared within the fi/A4 amino acid sequence to give short 40 amino-acid soluble derivatives. It seems that under some circumstances as in Alzheimer s disease, APP is cleared either side of the fi/A4 sequence to release the 42/43 amino acid P/A4 which aggregates into the amyloid fibrils of a senile plaque (a). (See also Fig. 18.5.) Some factors, e.g. gene mutation, must stimulate this abnormal clearage leading to the deposition of P/A4 amyloid protein as plaques and tangles and the death of neurons (b)...

Figure 13.6. From left to right location of the P-amyloid region of amyloid precursor protein (APP) in relation to the neuronal membrane normal processing of APP inactivates P-amyloid abnormal processing of APP in Alzheimer s disease liberates intact P-amyloid.

Alzheimer s disease, Parkinson s disease, Huntington s disease and amyotrophic lateral sclerosis (ALS) are four prominent fatal neurodegenerative disorders that involve the death of specific populations of neurons (see details in respective chapters). Studies of patients and animal and culture models have provided considerable insight in the cellular and molecular mechanisms responsible for synaptic dysfunction and neuronal degeneration in each disorder [18], In Alzheimer s disease, abnormalities in proteolytic processing of the amyloid precursor protein, due to gene... 

Strong evidence suggests that the main constituent of the plaque, P-amyloid peptide (AP), exerts a prominent role in the cause, initiation and progression of AD. Thus AD appears to arise from the abnormal deposition of a protein. Ap is derived from proteolytic cleavage of amyloid precursor protein (APP), an integral membrane protein. APP is cleaved by the sequential actions of three unique proteases, called a-, p-, and y-secretases. Each secretase cleaves at a unique site (see figure 8.7). 

One idea is that neurons in some patients destined to have Alzheimer s disease have an abnormality in the DNA that codes for a protein called amyloid precursor protein (APP) (Fig. 12—16). The abnormal DNA starts a lethal chemical cascade in neurons (Figs. 12—17 and 12—18), ultimately resulting in Alzheimer s disease (Figs. 

FIGURE 12—16. The amyloid cascade hypothesis of Alzheimer s disease (part 1). A leading contemporary theory for the biological basis of Alzheimer s disease centers around the formation of beta amyloid. Perhaps Alzheimer s disease is essentially a disease in which the abnormal deposition of beta amyloid reaches the point of destroying neurons. Thus, Alzheimer s disease may be essentially a problem of too much formation of beta amyloid, or too little removal of it. One idea is that neurons in some patients destined to have Alzheimer s disease have an abnormality in the DNA that codes for a protein called amyloid precursor protein (APP). The abnormal DNA starts a lethal chemical cascade in neurons, beginning with the formation of an altered APP. 

FIGURE 12—18. The amyloid cascade hypothesis of Alzheimer s disease (part 3). Once beta amyloid deposits are formed from abnormal APP (amyloid precursor protein), the next step is that beta amyloid deposits form plaques and tangles in the neuron. 

Masliah E., Alford M., Mallory M., Rockenstein E., Moechars D., and van Leuven F. (2000). Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice. Exp Neurol. 163 381-387. 

Padovani A, Borroni B, Colciaghi F, et al. Abnormalities in the pattern of platelet amyloid precursor protein forms in patients with mild cognitive impairment and Alzheimer disease. Arch Neurol 2002 59(1) 71—75. 

Trauma-induced axonal injury (TAI)is an important feature of human TBI. Some investigations have reported that moderate hypothermia can also reduce the generation of traumatically induced axonal injury (6,13). In one study, moderate hypothermia (32°C/4 h) initiated 10 min or 25 min after injury significantly reduced the number of abnormally stained axonal profiles (6). A study by Koizumi and Povlishock (13) reported that posttraumatic hypothermia (32°C/1 h) initiated as late as 1 h after trauma significantly reduced the density of amyloid precursor protein (APP) immunoreacti ve damaged axons within the corticospinal tract. Together, these data indicate that posttraumatic hypothermia in two models of TBI provides substantial protection in terms of axonal... 

The role of copper in other disease states is being investigated. For Alzheimer s disease studies, it has been found that the amyloid precursor protein interacts with copper to produce increased oxidant damage, and trace amounts of copper promote the precipitation of the amyloid p protein. In familial myotrophic lateral sclerosis about a quarter of the cases are caused by inherited dominant mutations in the Cu/Zn superoxide dismutase that probably result in abnormal Cu binding and the generation of reactive oxygen species. Copper has also been proposed to be involved in prion metabolism and fimction however, whether or not this imphcates copper in the prion diseases is unclear at this time. ... 

The amyloid-(3 peptide (A(3) has been identified as a 4 kDa hydrophobic nonglycosylated peptide consisting of 39 3 amino acid residues. It is derived by specific endoproteolytic cleavages from a 700 amino acid residue-long membrane-associated glycoprotein, named amyloid precursor protein (APP) (Citron et al., 1996 Dickson, 1997). A(3 appears in bundles of amyloid fibrils surrounded by abnormal neurites, and is believed to be the major component of the vascular and plaque filaments in individuals with AD, elderly people, and trisomy 21 carriers (Down s Syndrome) (Head and Lott, 2004). 

In AD brain, stimulation of PlsEtn-PLA2 may produce a deficiency of docosa-hexaenoic acid, a m-3 long-chain polyunsaturated fatty acid, which increases viscosity and augments energy consumption (Farooqui, 2009b Ferrer, 2009). It is proposed that abnormal neural membrane composition may modify the activity of key enzymes that modulate the cleavage of the amyloid precursor protein to form toxic Ap (see below). 

AD plaques are extracellular deposits of aggregated amyloid-P (AP) peptide that is proteolytically derived from the P-amyloid precursor protein (APP). In vitro and in vivo studies have shown that APP abnormalities can affect synaptic vesicle and axonal transport. Axonal dysfunction might lead to impaired synaptic plasticity and reduced neuronal viability. 

Askanas V, McFerrin J, Baque S et al. (1996) Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle. Proc Natl Acad Sci USA 93(3), 1314-1319. 

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