Aβ38 in the Brains of Patients with Sporadic and Familial Alzheimer's Disease and Transgenic Mouse Models

Abstract

The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-β peptides (Aβ), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aβ peptides existing are generated by subsequent cleavage of the amyloid-β protein precursor (AβPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aβ40 and Aβ42, Aβ peptides with other C-termini such as Aβ38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against Aβ38 to analyze the distribution of this Aβ species in cases of sporadic and familial AD, as well as in the brains of a series of established transgenic AD mouse models. We found Aβ38 to be present as vascular deposits in the brains of the majority of sporadic AD cases, whereas it is largely absent in non-demented control cases. Aβ38-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aβ38-positive plaques not only among familial cases due to AβPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aβ38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AβPP, or combinations of AβPP, PSEN1, and tau transgenes.

Chemical imaging of evolving amyloid plaque pathology and associated Aβ peptide aggregation in a transgenic mouse model of Alzheimer’s disease

“…In line with these data, plaque pathology-associated deposition of multiple C-terminally truncated peptides (Ab1-37, Ab1-38, Ab1-39 and Ab1-40) was previously described for familial AD (FAD) cases with the Swedish APP mutation (Reinert et al 2014;Reinert et al 2016) as well as in various transgenic mouse models carrying this mutation (Hsiao et al 1996;Kawarabayashi et al 2001;Kuo et al 2001;Reinert et al 2016).…”

Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer’s disease and transgenic mouse models

“…Even though research has long been centered on Aβ peptides and reports on the accumulation of Aβ40 and Aβ42 are numerous, the deposition of the C-terminally truncated Aβ peptides shorter than 40 amino acids in sporadic and familial AD patients has not been thoroughly investigated in post-mortem tissue. Recent studies by Moro and colleagues [ 32 ], as well as by our group [ 44 ], reported Aβ38 to be abundantly deposited within the vasculature of SAD cases presenting severe CAA, as well as in various FAD cases with underlying APP and PSEN1 mutations. To the best of the authors’ knowledge, there are currently no studies available describing the immunohistochemical analysis of the C-terminally truncated species Aβ37 or Aβ39 in human AD cases or transgenic mouse models.…”

“…All three species have been reported to be present in cerebrospinal fluid (CSF) [ 40 , 55 ] and human plasma [ 27 ] and might be of importance to increase diagnostic accuracy when using CSF samples [ 47 ], but immunohistochemical analysis for C-terminally truncated Aβ species have so far only focused on Aβ38. For this species, Moro et al and our group recently reported abundant deposition in the vasculature in sporadic AD (SAD) cases presenting severe cerebral amyloid angiopathy (CAA), as well as within NP and vascular amyloid deposits of different FAD cases [ 32 , 44 ]. Our present study extends these findings by the analyses of the deposition of Aβ37 and Aβ39 in SAD, FAD and common animal models of the disease.…”

Cerebral white matter lesions – associations with Aβ isoforms and amyloid PET

“…Evidence favors the hypothesis that amyloid fibrils deposited in the vessel wall and senile plaques differ from each other, as the major species in CAA is Aβ39 or Aβ40, and in senile plaque Aβ42, although Aβ40 may also be present 23 24 . Similarly, Aβ38 seems to be predominantly located within the vasculature in postmortem brains of sporadic and familial AD patients 11 25 . Impaired vascular clearance of Aβ across the BBB and increased Aβ brain capillary deposition has been reported in transgenic mice producing low levels of the poorly cleared Dutch/Iowa mutant forms of Aβ, which are vasculotropic and rich in β-sheets 26 .…”