An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

Abstract

Amyloid~3protein (A/3), 39-43 amino acids long, is the principal constituent of the extracellular amybid deposits in brain that are characteristic of Alzheimer's disease (AD). Several lines of evidence indicate that A~3 may play an important role in the pathogenesis of AD. However, there are several discrepancies between the production of A/3 and the development of the disease. Thus, A/may not be the sole active fragment of~3-amybid precursor protein (~3APP) in the neurotoxicity associated with AD. Consequently, the possible effects of other cleaved products of /3APP need to be explored. The recent concentration on other potentially amyloidogenic products of /IAPP has produced interesting candidates, the most promising of which are the amyloidogenic carboxyl-terminal (CT) fragments of~3APP. This review discusses a possible etiological role of CT fragments of /3APP in AD. Key Words: Amyloid precursor proteinCarboxyl-terminal peptide-Amyloid /3 protein -Etiological role-Alzheimer's disease. J. Neurochem. 68, 1781Neurochem. 68, -1791Neurochem. 68, (1997.Alzheimer' s disease (AD) is characterized by amybid deposits in senile plaques, in neurofibrillary tangles, and on the walls of cerebral blood vessels and dystrophic neurites, gliosis, and loss of neuronal synapses. various evidence indicates that amyloid~3pro-tein (A/3), which is a principal constituent of senile plaques (Glenner and Wong, 1984), may play an important role in the pathogenesis of AD (for review, see Selkoe, 1994;Checler, 1995). The A/I is composed of 39-43 amino acids and proteolytically derived from larger /3-amyloid precursor protein (/3APP) isoforms of 695, 714, 751, and 770 amino acids (Kang et al., 1987). Several mutations of /IAPP around the A/I domain have been discovered in certain types of earlyonset familial AD (FAD) (for review, see Tanzi et al., 1993), supporting its causal role in the pathogenesis of AD.To date, at least three processing pathways have been described: the nonamyloidogenic secretory pathway (a-secretase), which releases soluble ectodomain and prevents A/I formation (Esch et al., 1990); the endosomal-lysosomal pathway, in which some cell surface /IAPPs are reinternalized (Haass et al., 1 992a,b) and cleaved around at the N-terminus of the A/I sequence by /3-secretase to produce A/3-bearing amyloidogenic breakdown products of various sizes (14-22 kDa) Golde et al., 1992; Haass et al., 1992a,b;Shoji et al., 1992;Tamaoka et al., 1992) and subsequently possibly cleaved by 'ysecretase to release soluble 4-kDa A/I (Koo and Squazzo, 1994); and the 4-kDa A/I-producing pathway (/3-and y-secretases), involving coated pit-mediated endocytosis, which may be independent of the constitutive secretory pathway (Koo and Squazzo, 1994).Classically, A/I is the marker for AD, and it has been linked to the accompanying neurodegeneration (see, e.g., Sisodia et al., 1990). Several lines of evidence suggest that the overexpression of /3APP and the subsequent production of A/I could be linked to the genesis of AD (for review, see ...

Use-Dependent Effects of Amyloidogenic Fragments of β-Amyloid Precursor Protein on Synaptic Plasticity in Rat HippocampusIn Vivo

“…We have previously reported (Wu et al, 1995a) that intracellular application of A␤1-40 had the same ability to enhance NMDA receptormediated synaptic transmission as when applied exogenously. Similarly, CT can elicit strong inward currents when injected inside as well as outside cells (Fraser et al, 1997;Suh, 1997). It seems reasonable therefore to expect that actions similar to those reported here may apply to the effects of raised levels of intracellular ␤-APP metabolites on synaptic plasticity.…”

“…For example, a critical rise in postsynaptic Ca 2ϩ is required for LTD induction . All of the amyloidogenic ␤-APP fragments have been reported to enhance Ca 2ϩ entry or destabilize intracellular Ca 2ϩ storage (Fraser et al, 1997;Mattson, 1997;Suh, 1997;Kim et al, 2000). Such an action would be expected to facilitate LTD induction.…”

“…Subsequently, this is cleaved intramembrane by ␥-secretase to yield A␤. Both CT and A␤1-42 are particularly amyloidogenic and highly neurotoxic (Suh, 1997;Selkoe, 1999;Lu et al, 2000). Transgenic mice overexpressing wild-type and mutant ␤-APP show evidence of disruption of synaptic morphology, altered excitatory synaptic transmission or plasticity, and impairment of learning, often before amyloid plaque deposition (Nalbantoglu et al, 1997;Baekelandt et al, 1999;Chapman et al, 1999;Hsia et al, 1999;Larson et al, 1999;Moechars et al, 1999;Janus et al, 2000;Kumar-Singh et al, 2000;Mucke et al, 2000;Van Leuven, 2000).…”

Pathophysiological Roles of Amyloidogenic Carboxy-Terminal Fragments of the β-Amyloid Precursor Protein in Alzheimer’s Disease

“…To date, the cause and progression of both familial and sporadic (late-onset) AD have not been fully elucidated. Proteolytic processing of APP by b-, g-secretase, and caspases generates Ab and carboxy-terminal fragments of APP (CTFs), which have been implicated in the patho-genesis of AD (6,7). The missense mutations in the gene encoding APP, as well as in the genes encoding PS-1 and PS-2, share the common feature that they alter the g-secretase cleavage of APP to increase the production of the amyloidogenic Ab42, a primary component of amyloid plaques in both familial and sporadic AD.…”

Acetylcholinesterase Inhibitory Effect of 3-(1h-Indol-3-Yl)-1, 3-Diphenylpropan-1-One Derivatives

“…Production and accumulation of Aβ appear to be central to the pathogenesis of AD [26]. Aβ is a short polypeptide of about 42 amino acids produced by the abnormal proteolytic cleavage of amyloid precursor protein, which involves enzymes-like gammasecretase [27]. Production and deposition of Aβ are the central event triggering oxidation, lipid peroxidation, and excessive excitotoxicity of glutamatergic neurons, inflammation, apoptotic cell death, and formation of neurofibrillary tangles [26].…”