Geon Neurodegeneration:
From BDNF Deficiency to Hyperexcitability



This paper presents evidence for the BDNF Cascade Hypothesis which posits that neurodegeneration is fundamentally caused by neuronal hyperexcitability resulting from BDNF deficiency and other risk factors involved in the pathogenic cascade. The BDNF deficiency occurring in different brain areas may lead to distinct neurodegenerative diseases. Alzheimer's disease arises from BDNF deficiency in the lateral entorhinal cortex while amyotrophic lateral sclerosis may originate from BDNF deficiency in the motor cortex. Within the basal ganglia, BDNF deficiency could lead to either Parkinson's disease (PD) or progressive supranuclear palsy (PSP), depending on whether hyperexcitability is induced by hyperactive GSK-3β or elevated Tau level. Tau or GSK-3β induced hyperexcitability also distinguishes Tau-positive frontotemporal dementia from Dementia with Lewy Bodies that originate in the frontotemporal cortex. The GSK-3β induced hyperexcitability does not cause significant Tau pathology. This explains why PD exhibits little Tau pathology compared to PSP which is a tauopathy with symptoms resembling PD


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