Autophagy is markedly impaired in Alzheimer’s disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models.

β-amyloid precursor protein (APP) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked APP-βCTF generated by BACE1 (β-APP cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial BACE1 genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome (DS). Partially reducing BACE1 by deleting one BACE1 allele blocked development of age-related endosome enlargement in the medial septal nucleus (MSN), cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive MSN neurons. BACE1 reduction normalized APP-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for APP-βCTF in the development of these abnormalities. While ameliorative effects of BACE1 inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of BACE1 modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in DS and AD.

Fetal alcohol spectrum disorders (FASD) are associated with cognitive and behavioral deficits, and decreased volume of the whole brain and cerebral cortex. Rodent models have shown that early postnatal treatments, which mimic ethanol toxicity in the third trimester of human pregnancy, acutely induce widespread apoptotic neuronal degeneration and permanent behavioral deficits. However, the lasting cellular and anatomical effects of early ethanol treatments are still incompletely understood. This study examined changes in neocortex volume, thickness, and cellular organization that persist in adult mice after postnatal day 7 (P7) ethanol treatment. Post mortem brain volumes, measured by both MRI within the skull and by fluid displacement of isolated brains, were reduced 10–13% by ethanol treatment. The cerebral cortex showed a similar reduction (12%) caused mainly by lower surface area (9%). In spite of these large changes, several features of cortical organization showed little evidence of change, including cortical thickness, overall neuron size, and laminar organization. Estimates of total neuron number showed a trend level reduction of about 8%, due mainly to reduced cortical volume but unchanged neuron density. However, counts of calretinin (CR) and parvalbumin (PV) subtypes of GABAergic neurons showed a striking >30% reduction of neuron number. Similar ethanol effects were found in male and female mice, and in C57BL/6By and BALB/cJ mouse strains. Our findings indicate that the cortex has substantial capacity to develop normal cytoarchitectonic organization after early postnatal ethanol toxicity, but there is a selective and persistent reduction of GABA cells that may contribute to the lasting cognitive and behavioral deficits in FASD.

Highlights d Pathological Rab5 activation in PA-Rab5 mice mimics AD-like endosomal dysfunction d PA-Rab5 mice have synaptic function/structure deficits and GSK-3b-mediated tauopathy d Rab5 overactivation in vivo underlies cholinergic degeneration and memory deficits d Endosomal dysfunction alone induces prodromal and degenerative AD-related changes

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-d-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL−/− deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/− mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.