Alzheimer’s disease

Neurogranin and BACE1

Neurogranin (Ng) is a postsynaptic protein which is mainly expressed in the cortex and hippocampus and is localised in the dendritic spines. It is a potential biomarker of the loss of the synaptic integrity in the course of Alzheimer’s disease. Neurogranin plays a decisive role in the neuronal long-term potentiation and is therefore an important component of learning processes. In the CSF, mainly C-terminal fragments of neurogranin can be found, which are predominantly truncated by three amino acids (trunc 75). Studies showed that the neurogranin concentration in the brain of patients with Alzheimer’s disease was lower than that in healthy persons, whereas it was significantly increased in the CSF (De Vos et al., 2015; Kester et al., 2015). Moreover, an increased neurogranin level in the CSF proved to be predictive of a progression of Alzheimer’s disease from mild cognitive impairment (MCI) to dementia (Kester et al., 2015). Thus, neurogranin is a promising presymptomatic marker of synaptic damage.

BACE1 (beta-site APP cleaving enzyme 1, also β-secretase 1) is a presynaptic protein and a possible biomarker of neurodegenerative processes in the course of Alzheimer’s disease. BACE1 is a transmembrane aspartyl protease, which is also expressed in the brain. Its activity determines the speed of sequential proteolysis of the transmembrane amyloid precursor protein (APP) into Beta-Amyloid (1-42) (Aβ_1-42) resp. Beta-Amyloid (1-40) (Aβ_1-40). (Hampel et al., 2020).

De Vos et al. demonstrated that the ratio of the concentrations of neurogranin and BACE1 provides an even better prognostic value. In their study, an increased ratio was associated with a more rapid progression of the cognitive decline. This correlation was not observed for the classical markers of Alzheimer’s disease tau and Aβ (De Vos et al., 2016). In studies, patients with subjective cognitive decline (SCD) or MCI and confirmed amyloid pathology were also found to have a significantly higher Ng/BACE1 ratio than healthy persons (Kirsebom et al., 2018). Furthermore, the ratio enabled the differentiation of patients with Alzheimer’s disease from patients with major depressive disorder (MDD), despite similar cognitive deficits(Schipke et al., 2018).

Alpha-synuclein

Alpha-synuclein is a cytoplasmic protein which is concentrated in the presynaptic terminals. Its physiological function is not yet completely understood, but several studies suggest an involvement in vesicle trafficking and neurotransmitter release. Alpha-synuclein is associated with the development of synucleinopathies. These neurodegenerative diseases include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) (Goedert et al., 2017).

The majority of clinical studies show reduced concentrations in the CSF of patients with synucleinopathies compared to healthy persons and patients with other neurodegenerative diseases. In contrast, the alpha-synuclein concentration in the CSF of Alzheimer’s patients is significantly higher than in patients with synucleinopathies and in healthy controls. This was shown in several large-scale studies and may be specific for Alzheimer’s disease. When measuring alpha-synuclein in CSF it should be taken into account that the protein also occurs in peripheral blood and that up to 20 % of lumbar punctures are contaminated with blood (Mollenhauer et al., 2017; Vanderstichele et al., 2017).