Vossel, K. | bioRxiv Science

bioRxiv2022

Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease

BackgroundNeuronal and circuit level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (A{beta}) in preclinical models of Alzheimers disease (AD). These relationships remain poorly understood in patients with AD. MethodsUsing empirical spectra from magnetoencephalography (MEG) and computational modeling (neural mass model; NMM) we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and A{beta}, measured by positron emission tomography (PET), in patients with AD. ResultsPatients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher A{beta} depositions. ConclusionsOur results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and A{beta} in patients with AD. FundingThis study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM & GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimers Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL and (KGR); 2019-A-013-SUP (KGR); a grant from the Alzheimers Association: (PCTRB-13-288476) (KAV), and made possible by Part the CloudTM, (ETAC-09-133596); a grant from Tau Consortium (GDR & WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

neuroscience↗

bioRxiv2020

Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity

Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimers disease (AD). However, we understand very little about the normal functions of fission, or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid-precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+ (mitoCa2+) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa2+ overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.

neuroscience↗

bioRxiv2019

Taking the sub-lexical route: brain dynamics of reading in the semantic variant of Primary Progressive Aphasia.

Reading aloud requires mapping an orthographic form to a phonological one. The mapping process relies on sub-lexical statistical regularities (e.g., "oo" to |u{square}|) or on learned lexical associations between a specific visual form and a series of sounds (e.g., yacht to /j{square}t/). Computational, neuroimaging, and neuropsychological evidence suggest that sub-lexical, phonological and lexico-semantic processes rely on partially distinct neural substrates: a dorsal (occipito-parietal) and a ventral (occipito-temporal) route, respectively. Here, we investigated the spatiotemporal features of orthography-to-phonology mapping, capitalizing on the time resolution of magnetoencephalography and the unique clinical model offered by patients with semantic variant of Primary Progressive Aphasia (svPPA). Behaviorally, svPPA patients manifest marked lexico-semantic impairments including difficulties in reading words with exceptional orthographic to phonological correspondence (irregular words). Moreover, they present with focal neurodegeneration in the anterior temporal lobe (ATL), affecting primarily the ventral, occipito-temporal, lexical route. Therefore, this clinical population allows for testing of specific hypotheses on the neural implementation of the dualroute model for reading, such as whether damage to one route can be compensated by over-reliance on the other. To this end, we reconstructed and analyzed time-resolved whole-brain activity in 12 svPPA patients and 12 healthy age-matched controls while reading irregular words (e.g., yacht) and pseudowords (e.g., pook). Consistent with previous findings that the dorsal route is involved in sub-lexical, phonological processes, in control participants we observed enhanced neural activity over dorsal occipito-parietal cortices for pseudowords, when compared to irregular words. This activation was manifested in the beta-band (12-30 Hz), ramping up slowly over 500 ms after stimulus onset and peaking at [~]800 ms, around response selection and production. Consistent with our prediction, svPPA patients did not exhibit this temporal pattern of neural activity observed in controls this contrast. Furthermore, a direct comparison of neural activity between patients and controls revealed a dorsal spatiotemporal cluster during irregular word reading. These findings suggest that the sub-lexical/phonological route is involved in processing both irregular and pseudowords in svPPA. Together these results provide further evidence supporting a dual-route model for reading aloud mediated by the interplay between lexico-semantic and sub-lexical/phonological neuro-cognitive systems. When the ventral route is damaged, as in the case of neurodegeneration affecting the ATL, partial compensation appears to be possible by over-recruitment of the slower, serial attention-dependent, dorsal one. Abbreviated SummaryBorghesani et al. investigate brain dynamics during irregular word reading using magnetoencephalographic imaging in patients with semantic variant of primary progressive aphasia. Due to ventral anterior temporal lobe neurodegeneration, patients show greater reliance of dorsal, occipito-parietal brain regions - providing novel evidence for the interplay between ventral and dorsal routes for reading.

neuroscience↗