Intracellular Amyloid-β1–42, but Not Extracellular Soluble Amyloid-β Peptides, Induces Neuronal Apoptosis

Abstract

Alzheimer disease (AD), the most frequent cause of dementia, is characterized by an important neuronal loss. A typical histological hallmark of AD is the extracellular deposition of ␤-amyloid peptide (A␤), which is produced by the cleavage of the amyloid precursor protein (APP). Most of the gene mutations that segregate with the inherited forms of AD result in increasing the ratio of A␤42/A␤40 production. A␤42 also accumulates in neurons of AD patients. Altogether, these data strongly suggest that the neuronal production of A␤42 is a critical event in AD, but the intraneuronal A␤42 toxicity has never been demonstrated. Here, we report that the long term expression of human APP in rat cortical neurons induces apoptosis. Although APP processing leads to production of extracellular A␤1-40 and soluble APP, these extracellular derivatives do not induce neuronal death. On the contrary, neurons undergo apoptosis as soon as they accumulate intracellular A␤1-42 following the expression of full-length APP or a C-terminal deleted APP isoform. The inhibition of intraneuronal A␤1-42 production by a functional ␥-secretase inhibitor increases neuronal survival. Therefore, the accumulation of intraneuronal A␤1-42 is the key event in the neurodegenerative process that we observed.A clear diagnosis of AD 1 can be performed by correlating clinical findings and postmortem examination of brain sections. AD is characterized by a massive neuronal loss in vulnerable brain regions (1, 2). Two typical hallmarks of AD are neurofibrillary tangles and senile plaques (3). The major constituent of the amyloid core of senile plaques is the ␤-amyloid or A␤ peptide. The A␤ peptide is a 39 -43-amino acid peptide produced from a larger precursor, the amyloid precursor protein or APP (4). Among the ten identified isoforms of human APP (5), eight contain the A␤ sequence. The isoform that is mainly expressed in the human brain is a 695-amino acid protein known as APP695 (4). APP is processed by the non-amyloidogenic pathway, where ␣Ϫsecretase activity (6) produces soluble forms of APP, and by the amyloidogenic pathway, where ␤-secretase (7) and ␥-secretase activities allow the release of A␤. Several identified mutations in the APP and the presenilins genes segregate with inherited forms of AD known as early onset familial Alzheimer disease or FAD (8, 9). Most of these mutations result in an increased production of the A␤ ending at position 42 (10). In vitro studies have shown that A␤42 rapidly aggregates into fibrils and that extracellular fibrillar A␤ peptides induce apoptosis in cultured neurons (11). On the other hand, recent reports have demonstrated an intraneuronal accumulation of A␤42 in AD-vulnerable brain regions (12, 13). Intraneuronal A␤42 accumulation has also been reported in transgenic mice expressing FAD proteins (14) as well as in transgenic mice showing accelerated neurodegeneration without extracellular amyloid deposition (15). Altogether, these data support the idea that A␤42 accumulation and neuronal loss are closely correlated. N...

An alternative interpretation of the amyloid Aβ hypothesis with regard to the pathogenesis of Alzheimer's disease

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Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability

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Immunophenotypes in the circulation of patients with mild cognitive impairment

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