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bioRxiv · 10.1101/2025.01.07.630516

Early amyloid spine response and impaired synaptic transmission of pyramidal neurons in human biopsies with Alzheimer's Disease-related pathology

Dougalis, A.·Abushik, P.·Pelkonen, A.·Giudice, L.·Gomez-Budia, M.·Novosolova, N.·Valimaki, N.-N.·Rezaie, M.·Nurkhametova, D.·Giniatullina, R.·Shakirzyanova, A.·Mali, A.·Rauramaa, T.·Stevens, B.·Hiltunen, M.·Leinonen, V.·Malm, T.
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Abstract

Studies of neuronal functions during the pathological progression of Alzheimers disease (AD) in humans are limited due to the lack of live human brain tissue from patients with AD. To address this gap, we have established an exceptional approach to study the electrophysiological properties and cell morphologies of human neurons in acute slices obtained from cortical biopsies of patients with idiopathic normal pressure hydrocephalus (iNPH). Histological examination of Broadman area 8-9 cortical biopsies from these patients have revealed that approximately 40% of the patients show signs of early AD-related pathology in the form of low to moderate, often fleecy beta-amyloid (A{beta}) deposits and additional, occasional tau in 10% of the cases. Thus, the iNPH brain biopsies, obtained during the shunt surgery to treat the patients, offer a unique window to investigate how existing AD-related pathology alters the operational properties of human cortical neurons. Here we carried out integrative analysis of human neuronal electrophysiology at single neuron and network level followed by subsequent cellular morphological reconstructions to register the primary pathological changes in neuronal functions in correlation with existing AD-related pathology. The presence of A{beta} plaques induced a decrease in basal excitatory synaptic activity in pyramidal neurons residing on supragranular layers of the cortex. These neurons received less of L1-induced inhibition and appeared hyperexcitable in response to application to NMDA in multielectrode array (MEA) recordings. Interestingly, the global spine density of supraganular pyramidal neurons was increased in biopsies with AD-related pathology. The increase in spine density was coincidental with a partial recovery of excitatory transmission (frequency but not amplitude), of L1-induced inhibition in supragranular layers pyramidal neurons and of NMDA induced supragranular firing (but not of bursting hyperexcitability) indicating a potential differential effect of tau in the presence of A{beta} on the progression of neuronal functions. Despite the partial renormalization of deficits seen in cases with A{beta} pathology only, pyramidal neurons in cases with both A{beta} and tau exhibited more consistent deficits in the intrinsic neuronal properties with increase in sodium and potassium currents and a strong propensity to bursting under NMDA stimulation. We conclude that complex mechanisms operate in response to accumulation of A{beta} and tau including re-structuring of the apparatus of synaptic transmission and consolidation of a hyperexcitable supragranular cortical network phenotype. The observed changes in spine density and synaptic activity are reminiscent of parallels seen in homeostatic plasticity and synaptic scaling and may depend on strong interactions with the local microenvironment (astrocytes and microglia). This is the first study to report the impact of AD-related pathology on single-neuron operational properties and morphology in humans.

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Dougalis, A., Abushik, P., Pelkonen, A., Giudice, L., Gomez-Budia, M., Novosolova, N., Valimaki, N.-N., Rezaie, M., Nurkhametova, D., Giniatullina, R., Shakirzyanova, A., Mali, A., Rauramaa, T., Stevens, B., Hiltunen, M., Leinonen, V., Malm, T.. 2025-01-07. Early amyloid spine response and impaired synaptic transmission of pyramidal neurons in human biopsies with Alzheimer's Disease-related pathology. https://doi.org/10.1101/2025.01.07.630516

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