Abstract
Familial Alzheimer’s Disease (FAD) caused by Presenilin-1 (PS1) mutations is characterized by early onset, cognitive impairment, and dementia. Impaired gamma secretase function favors production of longer beta-amyloid species in PS1 FAD. The PS1 E280A mutation is the largest FAD kindred under study. Here, we studied beta-amyloid deposits in PS1 E280A FAD brains in comparison to sporadic Alzheimer’s disease (SAD). We analyzed cortices and cerebellum from 10 FAD and 10 SAD brains using immunohistochemistry to determine total beta-amyloid, hyperphosphorylated tau (pTau), and specific beta-amyloid peptides 1-38, 1-40, 1-42, and 1-43. Additionally, we studied beta-amyloid subspecies by ELISA, and vessel pathology was detected with beta-amyloid 1-42 and truncated pyroglutamylated beta-amyloid antibodies. There were no significant differences in total beta-amyloid signal between SAD and FAD. Beta-amyloid 1-38 and 1-43 loads were increased, and 1-42 loads were decreased in frontal cortices of SAD when compared to FAD. Beta-amyloid species assessment by ELISA resembled our findings by immunohistochemical analysis. Differences in beta-amyloid 1-38 and 1-42 levels between SAD and FAD were evidenced by using beta-amyloid length-specific antibodies, reflecting a gamma secretase-dependent shift in beta-amyloid processing in FAD cases. The use of beta-amyloid length-specific antibodies for postmortem assessment of beta-amyloid pathology can differentiate between SAD and PS1 FAD cases and it can be useful for identification of SAD cases potentially affected with gamma secretase dysfunction.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the elderly
The highest average immunosignal was detected in the frontal cortex of Familial Alzheimer’s Disease (FAD) as well as of sporadic Alzheimer’s disease (SAD) patients, followed by temporal cortex, parietal cortex, and occipital cortex, with the lowest Aβ signal being detected in the cerebellum (Figure 1B and Table 2), creating a predominantly frontal aggregation pattern (Figure 1C)
When individual aggregation patterns were analyzed, we found that 5/10 SAD and 7/10 FAD cases showed frontal cortex predominance
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the elderly. The prevalence is estimated to be about 24 to 35 million people worldwide (Reitz and Mayeux, 2014). It is characterized by progressive cognitive impairment and behavioral changes, which eventually lead to dementia and death (Giaccone et al, 2011). Age is one of the main risk factors for developing AD (Berr et al, 2005). The presence of allele 4 of Apolipoprotein E (ApoE4) is the main genetic risk factor for LOAD; ∼40% of these patients show at least one ApoE4 allele (Myers et al, 1996; Bettens et al, 2013)
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