Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier - phenotypic variability in autosomal dominant Alzheimer's disease - PubMed (original) (raw)

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Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier - phenotypic variability in autosomal dominant Alzheimer's disease

Grace M Lloyd et al. Acta Neuropathol Commun. 2020.

Abstract

The discovery of mutations associated with familial forms of Alzheimer's disease (AD), has brought imperative insights into basic mechanisms of disease pathogenesis and progression and has allowed researchers to create animal models that assist in the elucidation of the molecular pathways and development of therapeutic interventions. Position 717 in the amyloid precursor protein (APP) is a hotspot for mutations associated with autosomal dominant AD (ADAD) and the valine to isoleucine amino acid substitution (V717I) at this position was among the first ADAD mutations identified, spearheading the formulation of the amyloid cascade hypothesis of AD pathogenesis. While this mutation is well described in multiple kindreds and has served as the basis for the generation of widely used animal models of disease, neuropathologic data on patients carrying this mutation are scarce. Here we present the detailed clinical and neuropathologic characterization of an APP V717I carrier, which reveals important novel insights into the phenotypic variability of ADAD cases. While age at onset, clinical presentation and widespread parenchymal beta-amyloid (Aβ) deposition are in line with previous reports, our case also shows widespread and severe cerebral amyloid angiopathy (CAA). This patient also presented with TDP-43 pathology in the hippocampus and amygdala, consistent with limbic predominant age-related TDP-43 proteinopathy (LATE). The APOE ε2/ε3 genotype may have been a major driver of the prominent vascular pathology seen in our case. These findings highlight the importance of neuropathologic examinations of genetically determined AD cases and demonstrate striking phenotypic variability in ADAD cases.

Keywords: APOE; Alzheimer’s disease; Amyloid precursor protein; Beta-amyloid; Cerebral amyloid angiopathy; London mutation.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Fig. 1

(a) Representative chromatogram of Sanger-sequencing revealed a guanine-to-adenine single nucleotide substitution at codon 717 of APP, resulting in a Valine to Isoleucine amino acid change in the ADAD patient (APP NM_000484.3 c2149G > A pVal717Ile). (b, c) Representative gross images of formalin-fixed left hemibrain. (d - f) Representative overview (scale bar = 2000 μm) and high magnification (insert, scale bar = 50 μm) images of H&E stained sections reveal neuron loss, astrogliosis and numerous neuritic plaques (d), superficial spongiosis (e), as well as substantial amyloid angiopathy of superficial cortical and leptomeningeal vessels (f)

Fig. 2

Fig. 2

Representative images of 4G8-stained sections of mid-frontal cortex (a), superior temporal gyrus (b), visual cortex (c), cingulate gyrus (d), amygdala (e) and cerebellum (f) reveal widespread parenchymal and vascular (inserts) Aβ-pathology throughout the neuroaxis. Cerebral amyloid angiopathy was more prominent in cortical and leptomeningeal vasculature with no substantial involvement of cortical capillaries. Overview images (scale bar = 1000 μm) and high magnification insert (scale bar = 50 μm)

Fig. 3

Fig. 3

Representative overview (scale bar = 2000 μm) and high magnification (insert, scale bar = 50 μm) images of AT8 staining in APP V717I mutation carrier for the hippocampus (a), superior temporal gyrus (b) and visual cortex (c) reveal substantial NFT pathology in all regions examined. (d) AT8 staining also reveals “frequent” neuritic plaques in the inferior temporal cortex (scale bar = 1000 μm, insert scale bar = 50 μm). Representative overview (scale bar = 2000 μm) and high magnification (insert, scale bar = 50 μm) images of TDP-43 staining demonstrate TDP-43 positive inclusions in hippocampus (e) and amygdala (f)

Fig. 4

Fig. 4

(a - c) Representative images of superior temporal cortex sections of APP V717I mutation carrier labelled with pan-Aβ (4G8, a) antibodies, demonstrate strong labeling of parenchymal and vascular amyloid deposits. Vascular deposits also showed strong staining with Aβ1–42 specific antibodies (12F4, b) and Aβ1–40 specific antibodies (13.1.1, c). Parenchymal amyloid deposits demonstrated strong Aβ1–42 positivity (12F4, b), while being scarcely labelled with Aβ1–40 specific antibodies (13.1.1, c). Vascular amyloid in two SAD cases with different APOE genotype (ɛ3/ɛ3 (d-f) and ɛ4/ɛ4 (g-i)), showed a similar staining pattern with strong positivity for pan-Aβ antibodies (4G8, d, g), as well as Aβ1–42 (e, h) and Aβ1− 40 specific antibodies (f, i). Parenchymal amyloid in SAD cases were highlighted with pan-Aβ (d, g) and Aβ1–42 specific antibodies (e, h), and showed some reactivity with Aβ1–40 specific antibodies (f, i). Overview images (scale bar = 100 μm)

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