Interactions between amyloid, amyloid precursor protein, and mitochondria

Abstract

Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), of which Aβ is generated from, is found within mitochondria. Studies suggest Aβ can be generated in mitochondria and imported into mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. The role these interactions contribute to AD pathology and progression are unknown. Here, we discuss prior research, the rigor of those studies, and the critical knowledge gaps of relationships between APP, Aβ, and mitochondria.

Pathological convergence of APP and SNCA deficiency in hippocampal degeneration of young rats

“…A detailed description of MAM-localized APP and α-synuclein is shown in Fig. 6F , which is similar to other group [ 51 ].…”

Exosomal Dynamics and Brain Redox Imbalance: Implications in Alzheimer’s Disease Pathology and Diagnosis

“…Aβ has been shown to bind to mitochondrial short-chain alcohol dehydrogenase, known as Aβ-binding alcohol dehydrogenase (ABAD), as well as heat shock protein 60 (Hsp60), in the mitochondrial matrix [ 78 ]. The accumulation of Aβ may also inhibit the mitochondrial peptidasome (PreP), impacting the processing of mitochondrially targeted protein presequences and leading to multiple functional mitochondrial anomalies [ 79 ]. In addition, soluble Aβ oligomers can impair mitochondrial functions, possibly due to interactions with various mitochondrial proteins, including adenine nucleotide translocase, components of the translocase of the outer membrane (TOM) as well as inner membrane (TIM), and cyclophilin D [ 80 ].…”

Biomarkers associated with the pathogenesis of Alzheimer’s disease

“…The sAPPβ fragment is released into the extracellular matrix, and C99 is membrane-bound to the 99 amino acids at the C-terminal of APP ( Takasugi et al, 2023 ). Multiple sites of γ-secretase’s subsequent processing of C99 result in the discharge of the Aβ42 ( Figure 1 ; Roher et al, 2017 ; Suzuki et al, 2023 ; Takasugi et al, 2023 ; Wilkins, 2023 ). Aβ40 contains 40 amino acids, and Aβ42 contains 42 amino acids.…”

“…Aβ and tau are localized in mitochondria, and Aβ and tau have a direct synergistic toxic effect on synaptic mitochondria ( Mamun et al, 2020 ). At present, neurotoxic drugs targeting Aβ and tau proteins alone have not achieved significant efficacy, so a separate focus on the role of tau or Aβ in AD pathogenesis may not be entirely correct ( Wilkins, 2023 ). It has been shown that in brain tissue samples from APP transgenic mice, Aβ preferentially associates with the mitochondria of neurons and the high energy demand site rich in synapses in the hippocampus ( Nabi et al, 2022 ).…”