Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression

Abstract

The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer’s disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples.

Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations

“…Furthermore, a recent study found a correlation between Aβ peptide length and plaque load (Aβ 1-43 > Aβ 1-42 > Aβ 1-40 ), indicating that longer Aβ peptides have an increased tendency towards accumulation in the brain [23], thus explaining their lower CSF levels. Further analysis of the shorter Aβ species Aβ 1-41 , Aβ 1-37 (from Aβ 1-43 ) Aβ 1-38 (from Aβ 1-42 ) and Aβ 1-34 (from either Aβ 1-43 or Aβ 1-42 ) are however needed to better clarify the role of longer Aβ peptides in AD and the pathogenic events linked to Aβ process, degradation and clearance in the presence of APP and PSENs mutations [9][10][11].…”

“…The latter undergoes additional cleavages by γ-secretase to generate a series of Aβ peptides 39-43 amino acids long, following two different pathways: Aβ 1-49 > Aβ 1-46 > Aβ 1-43 > Aβ 1-40 and Aβ 1-48 > Aβ 1-45 > Aβ 1-42 > Aβ 1-38 [8]. Shorter peptides can also be produced, including Aβ 1-41 from Aβ 1-43 [9] and Aβ 1-34 from either Aβ 1-42 or Aβ 1-40 [10], which is considered a biomarker of Aβ clearance and AD progression [11]. Pathogenic mutations in APP and PSEN1 and 2 (γ-secretase's catalytic subunits) are known to influence APP metabolism leading to the deposition of Aβ peptides.…”

The amyloid-β degradation intermediate Aβ34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer’s disease

“…This additional BACE1 mediated cleavage can only take place with Aβ peptides as substrates implying that BACE1 indeed acts as an Aβ40/42 degrading enzyme to generate Aβ34 [19, 50]. In a recent study, we were able to show that Aβ34 levels are directly affected by over-expression or inhibition of BACE1 both in vitro and in vivo, and that cerebral BACE1 is the critical factor for Aβ34 generation [30]. Supporting its proposed role as a biomarker for clearance in sporadic AD, CSF Aβ34 levels were found to be elevated in subjects with mild cognitive impairment (MCI) who later converted to AD dementia [30].…”

“…In a recent study, we were able to show that Aβ34 levels are directly affected by over-expression or inhibition of BACE1 both in vitro and in vivo, and that cerebral BACE1 is the critical factor for Aβ34 generation [30]. Supporting its proposed role as a biomarker for clearance in sporadic AD, CSF Aβ34 levels were found to be elevated in subjects with mild cognitive impairment (MCI) who later converted to AD dementia [30]. Moreover, we also discovered a positive correlation between CSF Aβ34 levels and overall Aβ clearance rates in individuals with biomarker evidence of cerebral amyloid deposition [30].…”

Emerging Alternative Proteinases in APP Metabolism and Alzheimer’s Disease Pathogenesis: A Focus on MT1-MMP and MT5-MMP

“…However, a causal effect between β’-cleavage and neuroprotection is not straight forward as Aβ 11–40 is found in insoluble Aβ pools of post-mortem AD brains (Huse et al, 2002). More recently, it has been shown that BACE-1 can also cleave Aβ 40 or Aβ 42 to generate a C-terminal truncated Aβ 34 form, which appears to be a new biomarker of Aβ clearance in AD as it is noticeably increased in mild cognitive impaired patients along with strong BACE-1 activity (Liebsch et al, 2019). Together, these data confirm early studies (Fluhrer et al, 2003; Shi et al, 2003), placing BACE-1 as a prominent Aβ-generating, but also as an occasional Aβ-“degrading” enzyme under some circumstances.…”