APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38 (original) (raw)

Characterization of Aβ11-40/42 peptide deposition in Alzheimer’s disease and young Down’s syndrome brains: implication of N-terminally truncated Aβ species in the pathogenesis of Alzheimer’s disease

Acta Neuropathologica, 2006

Senile plaques (SPs), one of two deWning lesions of Alzheimer's disease (AD), are composed of a mixture of full-length A 1-40/42, and Nor C-terminally truncated A peptides, including A 11-40/42. Sequential proteolysis of amyloid precursor protein (APP) by-and-secretases produces A 1-40/42, but-site APPcleaving enzyme 1 (BACE1), the major-secretase, also generates A 11-40/42, and BACE1 overexpression in cultured cells results primarily in secretion of A 11-40/ 42. The ratio of A 11-40/42 to A 1-40/42 depends on the ratio of BACE1 to APP, and A 11-40/42 can be generated from both full-length APP and its carboxy-terminal fragment (C99). Here, we investigated the role of A 11-40/42 in the pathogenesis of AD and Down's syndrome (DS) brains. We demonstrated signiWcant amount of A 11-42 in DS brains by Western blots. While pyro-A 11-42-modiWed A species existed predominantly in mature SP cores in AD brain sections, both unmodiWed free A 11-40 and pyro-modiWed A 11-40 are detected in vascular amyloid deposits by immunohistochemistry. Using novel ELISAs for quantifying free A 11-40/42 and pyroA 11-40/42, we showed that insoluble A 11-42 predominated in extracts of AD and DS brains. This is the Wrst systematic study of A 11-40/42 in neurodegenerative A amyloidosis implicating A 11-40/42 in SP formation of AD and DS brains. The detection of A 11-42 in young DS brain suggests an early role for this N-terminally truncated A peptide in the pathogenesis of SPs in AD and DS.

Aβ43 is more frequent than Aβ40 in amyloid plaque cores from Alzheimer disease brains

Journal of Neurochemistry, 2009

Alzheimer disease (AD) is the most common form of dementia in the elderly. The earliest manifestation of the disease is impairment of memory and attention followed by deterioration of abstract thinking, language skills and alteration of personality. Brain regions involved in these processes are reduced in size as a result of the loss of synapses and neurons. The disease is at least partly caused by toxic oligomeric species formed by the amyloid b-peptide (Ab), which eventually are deposited in AD brains as amyloid plaques and in the walls of cerebral blood vessels (Glenner and Wong 1984; Masters et al. 1985). Numerous proteins have by immunohistochemistry been shown to associate with amyloid plaques, but the plaque cores are mainly composed of Ab (Söderberg et al. 2006). Amyloid b-peptide is derived from the amyloid precursor protein (APP) by sequential cleavage by b-secretase (BACE) (Vassar et al. 1999) and c-secretase. b-Secretase cleaves APP at the intraluminal/extracellular side, generating soluble APP and a 99-residue membrane bound fragment (C99). Subsequent cleavage of C99 by c-secretase, a transmembrane complex containing at least presenilin, nicastrin, anterior pharynx defective-1, and presenilin enhancer-2 (Gu et al.

Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation

Neurobiology of Disease, 1996

Patients with trisomy 21 [Down syndrome (DS)] progressively develop amyloid b-protein (Ab) deposits and then other features of Alzheimer's disease (AD), apparently due to increased gene dosage and thus expression of the b-amyloid precursor protein. Because the neuropathological phenotype in older DS subjects closely resembles that of AD, the examination of DS brains of increasing age provides a unique model of the progression of AD. Here, we characterized the deposition of several Ab peptides and apolipoprotein E in formalin-fixed brain sections from 29 DS subjects between 3 and 73 years old. Amyloid plaque number and the percentage of cortical area they occupied were quantified by computerized image analysis. Ab ending at amino acid 42 (Ab 42) was the earliest form of Ab deposited in DS cortex. It was observed in 7 of 16 young (3-30 years) subjects, with the earliest deposition occurring at age 12. Ab ending at residue 40 (Ab 40) was not detected until Dage 30, a time when degenerating neurites around Ab immunoreactive (IR) plaques were first observed, and the frequency of Ab 40 IR plaques then rose with age. Even in old (51-73 years) DS subjects, Ab 42 IR plaques were always more abundant than Ab 40 IR plaques. Ab peptides starting at aspartate 1 or pyroglutamate 3 were detected in small subsets of compacted, neuritic plaques beginning around age 30 and rose with age, the latter species always exceeding the former. Thus, the N-termini of the Ab 42 peptides abundantly deposited in very young DS subjects remain unknown. Apo E was detectable in a small subset of Ab 42 IR plaques beginning at age 12 and rose steadily with age; it clearly followed the deposition of Ab. Our analysis of very young DS brains suggests that amyloid plaque formation begins with Ab 42-ending peptides, and the number and percentage of cortical area of Ab 42 plaques increase very little with advancing age, while other heterogeneous Ab species and Apo E progressively accrue onto plaques containing Ab 42 .

Early amyloid -β deposits show different immunoreactivity to the amino- and carboxy-terminal regions of β-peptide in Alzheimer's disease and Down's syndrome brain

Neuroscience Letters, 1995

That the topography, severity, and progression of fl-amyloid deposition in the brain of Alzheimer's disease (AD) and Down's syndrome (DS) cases is not uniform is well documented. We have addressed at present, the issue of whether the structural composition of fl-peptide (Aft) within the early amyloid deposits might contribute to this phenomenon. The cerebral cortex, the caudate/putamen, and the cerebellum from 10 AD and 8 DS cases were immunostained with antibodies that recognize the 1-17; 17-24 amino acid residues of Aft, and the COOH-terminus of Aft42 variant, thus to the epitopes of Aft located amino-and carboxy-terminally to the site of the putative a-secretase cleavage. We demonstrate that numerous diffuse, early plaques in AD and especially in DS cases show predominance of the carboxy-terminally located epitopes of Aft; the most prominent in the cerebellum, less pronounced in the cerebral cortex, and only marginal, or absent in the striatum, except for some DS cases. These data suggest that the deposition of the carboxyterminal fragment of Aft truncated at the position of a-secretase cleavage or close to it in diffuse plaques may be brain-region-specific, reflecting either dissimilar processing of amyloid precursor protein or the resolution of early Aft deposits, and may substantially contribute to different progression offl-amyloidosis in various brain regions.