Abstract Body

Aims

To understand the drivers of different rates of progression in neurodegenerative diseases.

Abstract Body

Alzheimer's disease is categorized histopathologically by a fairly consistent stereotyped progression of amyloid deposits and neurofibrillary tangles across large domains of hte cerebrum, progressing from the first neuropathological lesions to severe involvement over several decades. By contrast, the clinical progression of the disease is enormously disparate - with a very long prodromal phase, then quite alot of variablility in age of clinical onset, rate of progression, and duration of illness. Genetic risk factors largely impact age of onset rather than rate of progression. Concurrent diseases that impact CNS function commonly are implicated in the clinical progression disparities, and indeed it is observed that the vast majority of elderly who die with "Alzheimer's disease" have at least one and often several other identifiable neurodegnerative markers, including Lewy bodies, TDP43, vascular lesions etc. Whether these are "incidental" or synergistic with Alzheimer lesions is uncertain.

We attacked the problem of why individuals with Alzheimer's disease have varied rates of progression by initially selecting individuals, both within our own Center and then in other populations, who had had autopsy confirmation of Alzheimer's disease in the absence of other identifiable lesions. Even in this selected population, there was substantial variablility in rate of progression of disease based on the research quality longitudinal records available. We found that tau isolated from the brains of these individuals had different biophysical properties, and different patterns of post translational modifications. The phosphorylation pattern, for example, accounted for some of the variance both in the clinical course of disease and in the bioactivity of the isolated tau from each brain. Similar results have been observed in a cohort of individuals with varying age of onset and rates of progression from teh Columbian PS1 kindred.

Another driver of disease variability may be genetic predispositon. Recent analyses support the idea that apoE4 genotype leads to both an earlier onset, and a more severe course, with the opposite the case with APOE2. We postulate that extent of inflammation, or an alteration in teh set point of inflammatory pathways, and vascular biology, might also act as drivers of disease.

Thus what we commonly call Alzheimer's disease may in fact be a common phenotype pathologically that had different drivers - from varied kinase activation leading to differential tau phosphorylation to other genetic and metabolic differences between individuals - and these different drivers may provide insight into design of clinical trials and ultiamtely into personalized medicine approaches to AD.

Methods

Evaluate cohorts of individuals who have been followed longitudinally from a clinical perspective, and have come to autopsy and are known to have had Alzheimer disease.

Results

Four separate studies reveal different types of drivers of rate of progression. A study of tau seeding properties in autopsy proven Alzheimer’s shows that various post-translational modifications occur in different individuals, and both the seeding properties and the post-translational modifications correlate well with the clinical rate of progression. Studies of a large cohort of individuals across the Alzheimer disease research centers NACC data base show that apoE genotype impacts both age of onset and rate of progression, with APOE2 leading to a slower rate of progression and APOE4 associated with a somewhat faster rate of progression, compared to APOE3 carriers. Analysis of available databases of RNA expression show that, among other factors, carriers of APOE4 differ from APOE3 in baseline neuroinflammatory characteristics, potentially linking genetic susceptibility with neuroinflammatory responses and . And recent data suggest that, at least in some individuals with Alzheimer disease, microvascular changes including inflammatory markers, angiogenic markers, and markers of senescence occur, potentially magnifying the known effects of vascular risk factors in the context of clinical progression.

Conclusions

Although we think of Alzheimer’s disease as a uniform pathophysiological entity, recent data suggest there may be different drivers of disease progression among individuals, highlighting the need to consider personalized medicine approaches to therapeutics.

Aims

The mechanism underlying learning and memory deficits in Alzheimer’s disease (AD) is not fully understood. The aim of this study was to elucidate the failure of memory formation in AD.

Abstract Body

Whether adult hippocampal neurogenesis plays a role in learning and memory deficits in Alzheimer’s disease (AD) is not known. Here we show that significantly less new neurons were recruited into a spatial recognition memory circuit in the hippocampus of a mouse model of familial Alzheimer’s disease (FAD) mice compared to wild type mice. Particularly, it is the number of recruited new neurons, but not the number of recruited mature granule neurons, that is impaired in the memory circuit in FAD. Following genetic augmentation of neurogenesis in FAD, new neurons were predominantly recruited into the memory circuit. Augmentation of hippocampal neurogenesis in FAD mice rescued memory deficits in spatial and contextual recognition, known to be compromised in AD. The number of new neurons recruited into the memory circuit correlated with behavioral performance. Chemogenetic inactivation of new neurons compromised memory retrieval. These results suggest that new neurons are essential for memory formation and impaired hippocampal neurogenesis in AD compromises this process leading to memory deficits.

Methods

We used genetic enhancement of hippocampal neurogenesis in FAD mice to examine its therapeutic efficacy. New neurons were chemogenetically manipulated to determine their role in memory circuit formation in AD.

Results

Here we show that significantly less new neurons were recruited into spatial recognition memory circuits in the hippocampus of a mouse model of familial Alzheimer’s disease (FAD) compared to wild type mice. Enhancement of neurogenesis in FAD led to more new neurons that were predominantly recruited into the memory circuit, as well as to the rescue of memory deficits. The number of new neurons recruited into the memory circuit correlated with behavioral performance. Importantly, inactivation of new neurons compromised memory retrieval.

Conclusions

These results suggest that new neurons play a role in memory formation and impaired hippocampal neurogenesis in AD compromises this process leading to memory deficits. Enhancing hippocampal neurogenesis may provide new therapeutic approach for the attenuation of cognitive deterioration in AD.

Aims

Our group and others have recently shown that the Amyloid Precursor Protein (APP) C-terminal fragment of 99 amino acids (APP-C99) accumulates in the brain of AD animal models and of sporadic and autosomal-dominant AD patients. The aim was to determine whether APP and APP-C99 accumulates within synapses in AD.

Methods

We applied Array Tomography (AT) in human AD tissue to investigate APP localization at synapses. We also isolated synaptosomal fractions from 40 frozen frontal cortex tissue blocks provided by the Neurological Tissue Brain Bank-IDIBAPS. We used postmortem brain samples of patients with sporadic AD (n=10), autosomal-dominant AD (n=10), Down syndrome with AD (n=10) and healthy controls without AD neuropathology (n=10). Using a commercially available assay (APP-B-CTF: IBL America) we measured APP-C99 levels in cerebral homogenates and in synaptosomal fractions across groups.

Results

Using array tomography we found that APP is localized at pre- and post-synaptic compartments in human AD brains. Our results demonstrated that there is a significant increase of APP-C99 accumulation (~2-fold) in synaptosomal fractions compared with brain homogenates in healthy controls. APP-C99 is also significantly increased in synaptosomal fractions of AD cases compared with healthy controls.

Conclusions

Our data reveal that APP is present and that APP-C99 accumulates, in synapses in AD. Our results suggest a potential role of APP-C99 in the synaptic damage in AD. Therapies aimed at mitigating APP-C99 accumulation could be potentially beneficial in AD.

Aims

Functional alterations in brain circuits characterized by increased neuronal synchrony are hallmarks of neuronal network dysfunction in both patients and mouse models of Alzheimer’s disease (AD). Here we address the potential role of Cl^- homeostasis dysregulation in the conversion of physiological sharp wave ripples (SWR) into pathological interictal epileptiform discharges (IED) in the hippocampal CA3 region of control and AD model mice.

Methods

Local field potential (LFP) activity was recorded in the CA3 of horizontal slices of 6-8 months old C57BL/6J (WT) or APP^NL/F knock-in mice. The expression of the K⁺/Cl⁻ cotransporter KCC2, was quantified by western blots from CA3 mini-slices obtained at the time of slice preparation. Prolonged Cl^- loading of CA3 pyramidal cells was achieved in a mouse line specifically expressing the chloride pump halorhodopsin (eNpHR3.0) in these neurons.

Results

SWR in the CA3 had higher amplitudes and rates of rise in APP^NL/F than in WT mice. In parallel, the expression of monomeric KCC2 was decreased in the APP^NL/F mice. Notably, the changes in SWR observed in slices of APP^NL/F mice could be replicated following Cl^- loading of CA3 pyramidal cells by prolonged (~10 min) activation of eNpHR3.0. The latter treatment also lead to the occurrence of IED in slices, much like those seen in CA3/CA1 LFP recordings in vivo in APP^NL/F mice at 6-8 months of age.

Conclusions

A lack of Cl^- extrusion in CA3 pyramidal neurons at early stages of AD may be a key contributor to the transition between SWR and IED.

Aims

(1) To study how tau pathology affects the activity of distinct neuronal cell types. (2) To study the functional consequences of astrocytic tau pathology.

Methods

We present AAV vectors expressing human truncated tau (amino acids 151-391/4R) and red fluorophore mCherry in equal ratio under the neuronal human synapsin promotor (AAV-hSyn-htTau) or the astrocytic GFAP promotor (AAV-GFAP-htTau). AAVs expressing mCherry under the same promotors were used as controls. AAVs were injected into the hippocampus of wild-type mice for histological, biochemical, and behavioral characterization.

AAV-hSyn-htTau was injected intracerebroventricularly in PV-Cre mice to study the effects of tau pathology on pyramidal neurons or interneurons using in vivo 2-photon calcium imaging. AAV-GFAP-htTau was injected into the cortex of wild-type or CX3CR1-YFP mice to study the effects of astrocytic tau pathology on neuronal activity or microglia using in vivo imaging, respectively.

Results

AAV-hSyn-htTau and AAV-GFAP-htTau both induced widespread expression of mCherry and hyperphosphorylated tau in neurons or astrocytes, respectively.

In vivo 2-photon calcium imaging of cortical neurons revealed increased activity in truncated tau-expressing PV+ interneurons, but not in pyramidal cells, suggesting that tau-mediated alteration of interneuron activity is an early pathological event. No cognitive impairments were detected at early timepoints.

Astrocytic tau pathology did not lead to detectable changes in cognition or neuronal spiking activity, but we observed morphological changes in microglia in vivo. Analysis of microglial motility is currently ongoing.

Conclusions

AAV-based tauopathy models are attractive tools to study the consequences of neuronal and glial tau pathology in vivo.

Funding

APVV 19/0585 and SyDAD (Horizon 2020, 676144)

Aims

We aim to investigate the interplay between gray matter (GM) and white matter (WM) neurodegeneration in subjective cognitive decline (SCD) individuals as a clinical risk factor for future cognitive impairment and dementia.

Methods

Subjective cognitive complaints were assessed in 225 cognitively unimpaired individuals from a community-based cohort. Neurodegeneration was assessed through measures of cortical thickness across the whole cortex and hippocampal volume for GM; and mean diffusivity (MD) for WM integrity across the whole brain WM. Mediation analysis and multiple linear regression were conducted to investigate the interplay between the measures of GM and WM neurodegeneration.

Results

Complaints were associated with reduced hippocampal volume, cortical thinning in several frontal and temporal areas and the insula, and worst WM integrity across the brain, with a tendency to spare the occipital lobe. SCD-related cortical thinning and worst WM integrity were associated with each other and jointly contributed to the complaints, but the contribution of cortical thinning to SCD was stronger.

Conclusions

We conclude that neurodegeneration processes affecting the GM and WM seem to be associated with each other in SCD and include brain areas other than those typically targeted by Alzheimer’s disease (AD). Our findings suggest that SCD may be a sensitive behavioral marker of heterogeneous brain pathologies in individuals recruited from the community. Future studies in SCD should extend imaging analysis to brain areas other than those typically involved in AD.